Dual-acting antihypertensive agents

ABSTRACT

The invention is directed to compounds having the formula: 
     
       
         
         
             
             
         
       
     
     wherein: Ar, r, Y, Z, Q, W, X, and R 5-7  are as defined in the specification, and pharmaceutically acceptable salts thereof. These compounds have AT 1  receptor antagonist activity and neprilysin inhibition activity. The invention is also directed to pharmaceutical compositions comprising such compounds; methods of using such compounds; and process and intermediates for preparing such compounds.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.60/925,931, filed on Apr. 24, 2007; the entire disclosure of which isincorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to novel compounds having angiotensin IItype 1 (AT₁) receptor antagonist activity and neprilysin-inhibitionactivity. The invention also relates to pharmaceutical compositionscomprising such compounds, processes and intermediates for preparingsuch compounds and methods of using such compounds to treat diseasessuch as hypertension.

2. State of the Art

The aim of antihypertensive therapy is to lower blood pressure andprevent hypertension-related complications such as myocardialinfarction, stroke, and renal disease. For patients with uncomplicatedhypertension (that is, no risk factors, target organ damage, orcardiovascular disease), it is hoped that reducing blood pressure willprevent development of cardiovascular and renal comorbidities,conditions that exist at the same time as the primary condition in thesame patient. For those patients with existing risk factors orcomorbidities, the therapeutic target is the slowing of comorbid diseaseprogression and reduced mortality.

Physicians generally prescribe pharmacological therapies for patientswhose blood pressure cannot be adequately controlled by dietary and/orlifestyle modifications. Commonly used therapeutic classes act topromote diuresis, adrenergic inhibition, or vasodilation. A combinationof drugs is often prescribed, depending upon what comorbidities arepresent.

There are five common drug classes used to treat hypertension:diuretics, which include thiazide and thiazide-like diuretics such ashydrochlorothiazide, loop diuretics such as furosemide, andpotassium-sparing diuretics such as triamterene; β₁ adrenergic receptorblockers such as metoprolol succinate and carvedilol; calcium channelblockers such as amlodipine; angiotensin-converting enzyme (ACE)inhibitors such as captopril, benazepril, enalapril, enalaprilat,lisinopril, quinapril, and ramipril; and AT₁ receptor antagonists, alsoknown as angiotensin II type 1 receptor blockers (ARBs), such ascandesartan cilexetil, eprosartan, irbesartan, losartan, olmesartanmedoxomil, telmisartan, and valsartan. Combinations of these drugs arealso administered, for example, a calcium channel blocker (amlodipine)and an ACE inhibitor (benazepril), or a diuretic (hydrochlorothiazide)and an ACE inhibitor (enalapril). All of these drugs, when usedappropriately, are effective in the treatment of hypertension.Nevertheless, both efficacy and tolerability should be further improvedin new drugs targeting hypertension. Despite the availability of manytreatment options, the recent National Health And Nutrition ExaminationSurvey (NHANES) demonstrated that only about 50% of all treated patientswith hypertension achieve adequate blood pressure control. Furthermore,poor patient compliance due to tolerability issues with availabletreatments further reduces treatment success.

In addition, each of the major classes of antihypertensive agents havesome drawbacks. Diuretics can adversely affect lipid and glucosemetabolism, and are associated with other side effects, includingorthostatic hypotension, hypokalemia, and hyperuricemia. Beta blockerscan cause fatigue, insomnia, and impotence; and some beta blockers canalso cause reduced cardiac output and bradycardia, which may beundesirable in some patient groups. Calcium channel blockers are widelyused but it is debatable as to how effectively these drugs reduce fataland nonfatal cardiac events relative to other drug classes. ACEinhibitors can cause coughing, and rarer side effects include rash,angioedema, hyperkalemia, and functional renal failure. AT₁ receptorantagonists are equally effective as ACE inhibitors but without the highprevalence of cough.

Neprilysin (neutral endopeptidase, EC 3.4.24.11) (NEP), is anendothelial membrane bound Zn²⁺ metallopeptidase found in many tissues,including the brain, kidney, lungs, gastrointestinal tract, heart, andperipheral vasculature. NEP is responsible for the degradation andinactivation of a number of vasoactive peptides, such as circulatingbradykinin and angiotensin peptides, as well as the natriureticpeptides, the latter of which have several effects includingvasodilation and diuresis. Thus, NEP plays an important role in bloodpressure homeostasis. NEP inhibitors have been studied as potentialtherapeutics, and include thiorphan, candoxatril, and candoxatrilat. Inaddition, compounds have also been designed that inhibit both NEP andACE, and include omapatrilat, gempatrilat, and sampatrilat. Referred toas vasopeptidase inhibitors, this class of compounds are described inRobl et al. (1999) Exp. Opin. Ther. Patents 9(12): 1665-1677.

There may be an opportunity to increase anti-hypertensive efficacy whencombining AT₁ receptor antagonism and NEP inhibition, as evidenced byAT₁ receptor antagonist/NEP inhibitor combinations described in WO9213564 to Darrow et al (Schering Corporation); US20030144215 to Ksanderet al.; Pu et al., Abstract presented at the Canadian CardiovascularCongress (October 2004); and Gardiner et al. (2006) JPET 319:340-348;and WO 2007/045663 (Novartis AG) to Glasspool et al.

Recently, WO 2007/056546 (Novartis AG) to Feng et al. has describedcomplexes of an AT₁ receptor antagonist and a NEP inhibitor, where anAT₁ receptor antagonist compound is non-covalently bound to a NEPinhibitor compound, or where the antagonist compound is linked to theinhibitor compound by a cation.

In spite of the advances in the art, there remains a need for a highlyefficacious monotherapy with multiple mechanisms of action leading tolevels of blood pressure control that can currently only be achievedwith combination therapy. Thus, although various hypertensive agents areknown, and administered in various combinations, it would be highlydesirable to provide compounds having both AT₁ receptor antagonistactivity and NEP inhibition activity in the same molecule. Compoundspossessing both of these activities are expected to be particularlyuseful as therapeutic agents since they would exhibit antihypertensiveactivity through two independent modes of action while having singlemolecule pharmacokinetics.

In addition, such dual-acting compounds are also expected to haveutility to treat a variety of other diseases that can be treated byantagonizing the AT₁ receptor and/or inhibiting the NEP enzyme.

SUMMARY OF THE INVENTION

The present invention provides novel compounds that have been found topossess AT₁ receptor antagonist activity and neprilysin (NEP) enzymeinhibition activity. Accordingly, compounds of the invention areexpected to be useful and advantageous as therapeutic agents fortreating conditions such as hypertension and heart failure.

One aspect of the invention is directed to a compound of formula I:

wherein: r is 0, 1 or 2;

Ar is selected from:

R¹ is selected from —COOR^(1a), —NHSO₂R^(1b), —SO₂NHR^(1d), —SO₂OH,—C(O)NH—SO₂R^(1c), —P(O)(OH)₂, —CN, —O—CH(R^(1e))—COOH, tetrazol-5-yl,

R^(1a) is H, —C₁₋₆alkyl, —C₁₋₃alkylenearyl, —C₁₋₃alkyleneheteroaryl,—C₃₋₇cycloalkyl, —CH(C₁₋₄alkyl)OC(O)R^(1aa), —C₀₋₆alkylenemorpholine,

R^(1aa) is —O—C₁₋₆alkyl, —O—C₃₋₇cycloalkyl, —NR^(1ab)R^(1ac), or—CH(NH₂)CH₂COOCH₃; R^(1ab) and R^(1ac) are independently selected fromH, —C₁₋₆alkyl, and benzyl, or are taken together as —(CH₂)₃₋₆—; R^(1b)is R^(1c) or —NHC(O)R^(1c); R^(1c) is —C₁₋₆alkyl,—C₀₋₆alkylene-O—R^(1ca), —C₁₋₅alkylene-NR^(1cb)R^(1cc),—C₀₋₄alkylenearyl or —C₀₋₄alkyleneheteroaryl; R^(1ca) is H, —C₁₋₆alkyl,or —C₁₋₆alkylene-O—C₁₋₆alkyl; R^(1cb) and R^(1cc) are independentlyselected from H and —C₁₋₆alkyl, or are taken together as—(CH₂)₂—O—(CH₂)₂— or —(CH₂)₂—N[C(O)CH₃]—(CH₂)₂—; R^(1d) is H, R^(1c),—C(O)R^(1c), or —C(O)NHR^(1c); R¹³ is —C₁₋₄alkyl or aryl;

Y is —C(R³)—, Z is —N—, Q is —C(R²)— and W is a bond; Y is —N—, Z is—C(R³)—, Q is —C(R²)— and W is a bond; Y is —C(R³)—, Z is —N—, Q is —N—and W is a bond; Y is —C(R³)—, Z is —CH—, Q is —N— and W is a bond; or Yis —C(R³)—, Z is —CH—, Q is —C(R²)— and W is —C(O)—;

R² is selected from H, halo, —NO₂, —C₁₋₆alkyl, —C₂₋₆alkenyl,—C₃₋₆cycloalkyl, —CN, —C(O)R^(2a), —C₀₋₅alkylene-OR^(2b),—C₀₋₅alkylene-NR^(2c)R^(2d), —C₀₋₃alkylenearyl, and—C₀₋₃alkyleneheteroaryl; where R^(2a) is selected from H, —C₁₋₆alkyl,—C₃₋₆cycloalkyl, —OR^(2b) and —NR^(2c)R^(2d); R^(2b) is selected from H,—C₁₋₆alkyl, —C₃₋₆cycloalkyl, and —C₀₋₄alkylenearyl; and R^(2c) andR^(2d) are independently selected from H, —C₁₋₄alkyl, and—C₀₋₁alkylenearyl;

R³ is selected from —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₃₋₁₀alkynyl,—C₀₋₃alkylene-C₃₋₇cycloalkyl, —C₂₋₃alkenylene-C₃₋₇cycloalkyl,—C₂₋₃alkynylene-C₃₋₇cycloalkyl,—C₀₋₅alkylene-NR^(3a)—C₀₋₅alkylene-R^(3b),—C₀₋₅alkylene-O—C₀₋₅alkylene-R^(3b),—C₀₋₅alkylene-S—C₁₋₅alkylene-R^(3b), and —C₀₋₃alkylenearyl; where R^(3a)is selected from H, —C₁₋₆alkyl, —C₃₋₇cycloalkyl, and —C₀₋₃alkylenearyl;and R^(3b) is selected from H, —C₁₋₆alkyl, —C₃₋₇cycloalkyl,—C₂₋₄alkenyl, —C₂₋₄alkynyl, and aryl;

X is —C₁₋₁₂alkylene-, where at least one —CH₂— moiety in the alkylene isreplaced with a —NR^(4a)—C(O)— or —C(O)—NR^(4a)— moiety, where R^(4a) isselected from H, —OH, and —C₁₋₄alkyl;

R⁵ is selected from —C₀₋₃alkylene-SR^(5a),—C₀₋₃alkylene-C(O)NR^(5b)R^(5e), —C₀₋₃alkylene-NR^(5b)—C(O)R^(5d),—NH—C₀₋₁alkylene-P(O)(OR^(5e))₂, —C₀₋₃alkylene-P(O)OR^(5e)R^(5f),—C₀₋₂alkylene-CHR^(5g)—COOH, —C₀₋₃alkylene-C(O)NR^(5h)—CHR^(5i)—COOH,and —C₀₋₃alkylene-S—SR^(5j); R^(5a) is H or —C(O)—R^(5aa); R^(5aa) is—C₀₋₆alkylene-C₃₋₇cycloalkyl, —C₀₋₆alkylenearyl,—C₀₋₆alkyleneheteroaryl, —C₀₋₆alkylenemorpholine,—C₀₋₆alkylenepiperazine-CH₃, —CH[N(R^(5ab))₂]-aa where aa is an aminoacid side chain, -2-pyrrolidine, —C₀₋₆alkylene-OR^(5ab),—O—C₀₋₆alkylenearyl, —C₁₋₂alkylene-OC(O)—C₁₋₆alkyl,—C₁₋₂alkylene-OC(O)—C₀₋₆alkylenearyl, or—O—C₁₋₂alkylene-OC(O)O—C₁₋₆alkyl; R^(5ab) is independently H or—C₁₋₆alkyl; R^(5b) is H, —OH, —OC(O)R^(5ba), —CH₂COOH, —O-benzyl,-pyridyl, or —OC(S)NR^(5bb)R^(5bc); R^(5ba) is H, —C₁₋₆alkyl, aryl,—OCH₂-aryl, —CH₂O-aryl, or —NR^(5bb)R^(5bc); R^(5bb) and R^(5bc) areindependently selected from H and —C₁₋₄alkyl; R^(5c) is H, —C₁₋₆alkyl,or —C(O)—R^(5ca); R^(5ca) is H, —C₁₋₆alkyl, —C₃₋₇cycloalkyl, aryl, orheteroaryl; R^(5d) is H, —C₁₋₄alkyl, —C₀₋₃alkylenearyl,—NR^(5da)R^(5db), —CH₂SH, or —O—C₁₋₆alkyl; R^(5da) and R^(5db) areindependently selected from H and —C₁₋₄alkyl; R^(5e) is H, —C₁₋₆alkyl,—C₁₋₃alkylenearyl, C₁₋₃alkyleneheteroaryl, —C₃₋₇cycloalkyl,—CH(CH₃)—O—C(O)R^(5ea),

R^(5ea) is —O—C₁₋₆alkyl, —O—C₃₋₇cycloalkyl, —NR^(5eb)R^(5ec), or—CH(NH₂)CH₂COOCH₃; R^(5eb) and R^(5ec) are independently selected fromH, —C₁₋₄alkyl, and —C₁₋₃alkylenearyl, or are taken together as—(CH₂)₃₋₆—; R^(5f) is H, —C₀₋₃alkylenearyl,—C₁₋₃alkylene-NR^(5fa)R^(5fb), or—C₁₋₃alkylene(aryl)-C₀₋₃alkylene-NR^(5fa)R^(5fb); R^(5fa) and R^(5fb)are independently selected from H and —C₁₋₄alkyl; R^(5g) is H,—C₁₋₆alkyl, —C₁₋₃alkylenearyl, or —CH₂—O—(CH₂)₂—O—CH₃; R^(5h) is H or—C₁₋₄alkyl; R^(5i) is H, —C₁₋₄alkyl, or —C₀₋₃alkylenearyl; and R^(5j) is—C₁₋₆alkyl, aryl, or —CH₂CH(NH₂)COOH;

R⁶ is selected from —C₁₋₆alkyl, —CH₂—O—(CH₂)₂—O—CH₃,—C₁₋₆alkylene-O—C₁₋₆alkyl, —C₀₋₃alkylenearyl, —C₀₋₃alkyleneheteroaryl,and —C₀₋₃alkylene-C₃₋₇cycloalkyl; and

R⁷ is H or is taken together with R⁶ to form —C₃₋₇cycloalkyl;

wherein: each —CH₂— group in —(CH₂)_(r)— is optionally substituted with1 or 2 substituents independently selected from —C₁₋₄alkyl and fluoro;each ring in Ar and each aryl and heteroaryl in R¹⁻³ and R⁵⁻⁶ isoptionally substituted with 1 to 3 substituents independently selectedfrom —OH, —C₁₋₆alkyl, —C₂₋₄alkenyl, —C₂₋₄alkynyl, —CN, halo,—O—C₁₋₆alkyl, —S—C₁₋₆alkyl, —S(O)—C₁₋₆alkyl, —S(O)₂—C₁₋₄alkyl, -phenyl,—NO₂, —NH₂, —NH—C₁₋₆alkyl and —N(C₁₋₆alkyl)₂, wherein each alkyl,alkenyl and alkynyl is optionally substituted with 1 to 5 fluoro atoms;each carbon atom in X is optionally substituted with one or more R^(4b)groups and one —CH₂— moiety in X may be replaced with a group selectedfrom —C₄₋₈cycloalkylene-, —CR^(4d)═CH—, and —CH═CR^(4d)—; wherein R^(4b)is selected from —C₀₋₅alkylene-COOR^(4c), —C₁₋₆alkyl,—C₀₋₁alkylene-CONH₂, —C₁₋₂alkylene-OH, —C₀₋₃alkylene-C₃₋₇cycloalkyl,1H-indol-3-yl, benzyl, and hydroxybenzyl, where R^(4c) is H or—C₁₋₄alkyl; and R^(4d) is selected from —CH₂-thiophene and phenyl; eachalkyl and each aryl in R¹⁻³, R^(4a-4d), R⁵⁻⁶ is optionally substitutedwith 1 to 7 fluoro atoms; and

pharmaceutically acceptable salts thereof.

Another aspect of the invention relates to pharmaceutical compositionscomprising a pharmaceutically acceptable carrier and a compound of theinvention. Such compositions may optionally contain other therapeuticagents such as diuretics, β₁ adrenergic receptor blockers, calciumchannel blockers, angiotensin-converting enzyme inhibitors, AT₁ receptorantagonists, neprilysin inhibitors, non-steroidal anti-inflammatoryagents, prostaglandins, anti-lipid agents, anti-diabetic agents,anti-thrombotic agents, renin inhibitors, endothelin receptorantagonists, endothelin converting enzyme inhibitors, aldosteroneantagonists, angiotensin-converting enzyme/neprilysin inhibitors,vasopressin receptor antagonists, and combinations thereof. Accordingly,in yet another aspect of the invention, a pharmaceutical compositioncomprises a compound of the invention, a second therapeutic agent, and apharmaceutically acceptable carrier. Another aspect of the inventionpertains to a combination of active agents, comprising a compound of theinvention and a second therapeutic agent. The compound of the inventioncan be formulated together or separately from the additional agent(s).When formulated separately, a pharmaceutically acceptable carrier may beincluded with the additional agent(s). Thus, yet another aspect of theinvention relates to a combination of pharmaceutical compositions, thecombination comprising: a first pharmaceutical composition comprising acompound of the invention and a first pharmaceutically acceptablecarrier; and a second pharmaceutical composition comprising a secondtherapeutic agent and a second pharmaceutically acceptable carrier. Theinvention also relates to a kit containing such pharmaceuticalcompositions, for example where the first and second pharmaceuticalcompositions are separate pharmaceutical compositions.

Compounds of the invention possess both AT₁ receptor antagonist activityand NEP enzyme inhibition activity, and are therefore expected to beuseful as therapeutic agents for treating patients suffering from adisease or disorder that is treated by antagonizing the AT₁ receptorand/or inhibiting the NEP enzyme. Thus, one aspect of the invention isdirected to a method of treating patients suffering from a disease ordisorder that is treated by antagonizing the AT₁ receptor and/orinhibiting the NEP enzyme, comprising administering to a patient atherapeutically effective amount of a compound of the invention. Anotheraspect of the invention is directed to a method of treating hypertensionor heart failure, comprising administering to a patient atherapeutically effective amount of a compound of the invention. Stillanother aspect of the invention pertains to a method for antagonizing anAT₁ receptor in a mammal comprising administering to the mammal, an AT₁receptor-antagonizing amount of a compound of the invention. Yet anotheraspect of the invention pertains to a method for inhibiting a NEP enzymein a mammal comprising administering to the mammal, a NEPenzyme-inhibiting amount of a compound of the invention.

Compounds of formula I and pharmaceutically acceptable salts thereof,that are of particular interest include those that exhibit an inhibitoryconstant (pK_(i)) for binding to an AT₁ receptor greater than or equalto about 5.0; in particular those having a pK_(i) greater than or equalto about 6.0; in one embodiment those having a pK_(i) greater than orequal to about 7.0; more particularly those having a pK_(i) greater thanor equal to about 8.0; and in yet another embodiment, those having apK_(i) within the range of about 8.0-10.0. Compounds of particularinterest also include those having a NEP enzyme inhibitory concentration(pIC₅₀) greater than or equal to about 5.0; in one embodiment thosehaving a pIC₅₀ greater than or equal to about 6.0; in particular thosehaving a pIC₅₀ greater than or equal to about 7.0; and most particularlythose having a pIC₅₀ within the range of about 7.0-10.0. Compounds offurther interest include those having a pK_(i) for binding to an AT₁receptor greater than or equal to about 7.5 and having a NEP enzymepIC₅₀ greater than or equal to about 7.0.

Since compounds of the invention possess AT₁ receptor antagonistactivity and NEP inhibition activity, such compounds are also useful asresearch tools. Accordingly, one aspect of the invention pertains to amethod of using a compound of the invention as a research tool, themethod comprising conducting a biological assay using a compound of theinvention. Compounds of the invention can also be used to evaluate newchemical compounds. Thus another aspect of the invention relates to amethod of evaluating a test compound in a biological assay, comprising:(a) conducting a biological assay with a test compound to provide afirst assay value; (b) conducting the biological assay with a compoundof the invention to provide a second assay value; wherein step (a) isconducted either before, after or concurrently with step (b); and (c)comparing the first assay value from step (a) with the second assayvalue from step (b). Exemplary biological assays include an AT₁ receptorbinding assay and a NEP enzyme inhibition assay. Still another aspect ofthe invention is directed to a method of studying a biological system orsample comprising an AT₁ receptor, a NEP enzyme, or both, the methodcomprising: (a) contacting the biological system or sample with acompound of the invention; and (b) determining the effects caused by thecompound on the biological system or sample.

The invention is also directed to processes and intermediates useful forpreparing compounds of the invention. Accordingly, another aspect of theinvention relates to a process of preparing compounds of the inventioncomprising the step of coupling a compound of formula 1 with a compoundof formula 2:

where: A is —NH₂ and B is —COOH or A is —COOH and B is —NH₂; the sum ofa and b is in the range of 0 to 11; Ar* represents Ar—R¹*, where R¹* isR¹ or a protected form of R¹; and R⁵* represents R⁵ or a protected formof R⁵; the carbon atoms in the —(CH₂)_(a) and —(CH₂)_(b) groups may besubstituted with one or more R^(4b) groups; and one —CH₂— group in the—(CH₂)_(a) or the —(CH₂)_(b) group may be replaced with—C₄₋₈cycloalkylene-, —CR^(4d)═CH—, or —CH═CR^(4d)—; and optionallydeprotecting the product when R¹* is a protected form of R¹ and/or R⁵*is a protected form of R⁵. Another aspect of the invention relates to aprocess of preparing a pharmaceutically acceptable salt of a compound offormula I, comprising contacting a compound of formula I in free acid orbase form with a pharmaceutically acceptable base or acid. In otheraspects, the invention is directed to products prepared by any of theprocesses described herein, as well as novel intermediates used in suchprocess. In one aspect of the invention novel intermediates have formulaVIII, IX or X.

Yet another aspect of the invention is directed to the use of a compoundof formula I or a pharmaceutically acceptable salt thereof, for themanufacture of a medicament, especially for the manufacture of amedicament useful for treating hypertension or heart failure. Anotheraspect of the invention is directed to use of a compound of theinvention for antagonizing an AT₁ receptor or for inhibiting a NEPenzyme in a mammal. Still another aspect of the invention pertains tothe use of a compound of the invention as a research tool. Other aspectsand embodiments of the invention are disclosed herein.

DETAILED DESCRIPTION OF THE INVENTION

The invention is directed to compounds of formula I:

and pharmaceutically acceptable salts thereof.

As used herein, the term “compound of the invention” is intended toinclude compounds of formula I as well as the species embodied informulas II-VI. In addition, the compounds of the invention may alsocontain several basic or acidic groups (for example, amino or carboxylgroups) and therefore, such compounds can exist as a free base, freeacid, or in various salt forms. All such salt forms are included withinthe scope of the invention. Furthermore, solvates of compounds offormula I or salts thereof are included within the scope of theinvention. Finally, the compounds of the invention may also exist asprodrugs. Accordingly, those skilled in the art will recognize thatreference to a compound herein, for example, reference to a “compound ofthe invention” includes reference to a compound of formula I as well asto pharmaceutically acceptable salts, solvates and prodrugs of thatcompound unless otherwise indicated. Further, the term “or apharmaceutically acceptable salt, solvate and/or prodrug thereof” isintended to include all permutations of salts and solvates, such as asolvate of a pharmaceutically acceptable salt.

The compounds of formula I may contain one or more chiral centers and somay exist in a number of stereoisomeric forms. When such chiral centersare present, the invention is directed to racemic mixtures, purestereoisomers (enantiomers or diastereomers), stereoisomer-enrichedmixtures, and the like unless otherwise indicated. When a chemicalstructure is depicted without any stereochemistry, it is understood thatall possible stereoisomers are encompassed by such structure. Thus, forexample, the term “compound of formula I” is intended to include allpossible stereoisomers of the compound. Similarly, when a particularstereoisomer is shown or named herein, it will be understood by thoseskilled in the art that minor amounts of other stereoisomers may bepresent in the compositions of the invention unless otherwise indicated,provided that the utility of the composition as a whole is noteliminated by the presence of such other isomers. Individual enantiomersmay be obtained by numerous methods that are well known in the art,including chiral chromatography using a suitable chiral stationary phaseor support, or by chemically converting them into diastereomers,separating the diastereomers by conventional means such aschromatography or recrystallization, then regenerating the originalenantiomers. Additionally, where applicable, all cis-trans or E/Zisomers (geometric isomers), tautomeric forms and topoisomeric forms ofthe compounds of the invention are included within the scope of theinvention unless otherwise specified.

Compounds of formula I may contain one or more chiral centers. Onepossible chiral center could be present in the “X” portion of thecompound. For example, a chiral center exists at a carbon atom in thealkylene moiety in X that is substituted with an R^(4b) group such as—C₁₋₆alkyl, for example —CH₃. This chiral center is present at thecarbon atom indicated by the symbol * in the following partial formula:

Another possible chiral center could be present at the carbon on the—X—CR⁵R⁶R⁷ group, when R⁶ is a group such as —C₁₋₆alkyl, for example—CH₂CH(CH₃)₂, and R⁷ is hydrogen. This chiral center is present at thecarbon atom indicated by the symbol ** in the following formula:

In one embodiment of the invention, the carbon atom identified by thesymbol * and/or ** has the (R) configuration. In this embodiment,compounds of formula I have the (R) configuration at the carbon atomidentified by the symbol * and/or ** or are enriched in a stereoisomericform having the (R) configuration at this carbon atom (or atoms). Inanother embodiment, the carbon atom identified by the symbol * and/or **has the (S) configuration. In this embodiment, compounds of formula Ihave the (S) configuration at the carbon atom identified by the symbol *and/or ** or are enriched in a stereoisomeric form having the (S)configuration at this carbon atom. It is understood that a compound mayhave a chiral center at both the * and the ** carbon atoms. In suchcases, four possible diastereomers can exist. In some cases, in order tooptimize the therapeutic activity of the compounds of the invention, forexample, as hypertensive agents, it may be desirable that the carbonatom identified by the symbol * and/or ** have a particular (R) or (S)configuration.

The compounds of the invention, as well as those compounds used in theirsynthesis, may also include isotopically-labeled compounds, that is,where one or more atoms have been enriched with atoms having an atomicmass different from the atomic mass predominately found in nature.Examples of isotopes that may be incorporated into the compounds offormula I, for example, include, but are not limited to, ²H, ³H, ¹³C,¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³⁵S, ³⁶Cl, and ¹⁸F.

The compounds of formula I have been found to possess AT₁ receptorantagonizing activity and NEP enzyme inhibition activity. Among otherproperties, such compounds are expected to be useful as therapeuticagents for treating diseases such as hypertension. By combining dualactivity into a single compound, double therapy can be achieved, thatis, AT₁ receptor antagonist activity and NEP enzyme inhibition activitycan be obtained using a single active component. Since pharmaceuticalcompositions containing one active component are typically easier toformulate than compositions containing two active components, suchsingle-component compositions provide a significant advantage overcompositions containing two active components. In addition, certaincompounds of the invention have also been found to be selective forinhibition of the AT₁ receptor over the angiotensin II type 2 (AT₂)receptor, a property that may have therapeutic advantages.

The nomenclature used herein to name the compounds of the invention isillustrated in the Examples herein. This nomenclature has been derivedusing the commercially available AutoNom software (MDL, San Leandro,Calif.).

REPRESENTATIVE EMBODIMENTS

The following substituents and values are intended to providerepresentative examples of various aspects and embodiments of theinvention. These representative values are intended to further defineand illustrate such aspects and embodiments and are not intended toexclude other embodiments or to limit the scope of the invention. Inthis regard, the representation that a particular value or substituentis preferred is not intended in any way to exclude other values orsubstituents from the invention unless specifically indicated.

The invention is directed to compounds of formula I:

In one embodiment, Y represents —C(R³)—, Z is —N—, Q is —C(R²)— and W isa bond. This embodiment of formula I can be represented by formula II:

In another embodiment, Y represents —C(R³)—, Z is —N—, Q is —N— and W isa bond. This embodiment of formula I can be represented by III:

In yet another embodiment, Y represents —C(R³)—, Z is —CH—, Q is —C(R²)—and W is —C(O)—. This embodiment of formula I can be represented by IV:

In yet another embodiment, Y represents —N—, Z is —C(R³)—, Q is —C(R²)—and W is a bond.This embodiment of formula I can be represented by V:

In another embodiment, Y represents —C(R³)—, Z is —CH—, Q is —N— and Wis a bond. In this embodiment, formula I can be represented as thesubgenus VI:

In particular embodiments, Y represents —C(R³)—, Z is —N—, Q is —C(R²)—and W is a bond, or Y is —C(R³)—, Z is —N—, Q is —N— and W is a bond.

The values for r are 0, 1 or 2. In one embodiment, r is 1. Each —CH₂—group in the —(CH₂)_(r)— group may be substituted with 1 or 2substituents independently selected from —C₁₋₄alkyl (for example, —CH₃),and fluoro. In one particular embodiment, the —(CH₂)_(r)-group isunsubstituted; in another embodiment, one or two —CH₂— groups in—(CH₂)_(r)— are substituted with a —C₁₋₄alkyl group.

Ar represents an aryl group selected from:

Each ring in the Ar moiety may be substituted with 1 to 3 substituentsindependently selected from —OH, —C₁₋₆alkyl, —C₂₋₄alkenyl, —C₂₋₄alkynyl,—CN, halo, —O—C₁₋₆alkyl, —S—C₁₋₆alkyl, —S(O)—C₁₋₆alkyl,—S(O)₂—C₁₋₆alkyl, -phenyl, —NO₂, —NH₂, —NH—C₁₋₆alkyl and —N(C₁₋₆alkyl)₂.Furthermore, each of the aforementioned alkyl, alkenyl and alkynylgroups are optionally substituted with 1 to 5 fluoro atoms.

In one particular embodiment, each ring in the Ar moiety may besubstituted with 1 to 2 substituents independently selected from —OH,—C₁₋₄alkyl (for example, —CH₃), halo (for example bromo, fluoro, chloro,and di-fluoro), —O—C₁₋₄alkyl (for example, —OCH₃), and -phenyl.Exemplary substituted Ar moieties include:

Of particular interest is where Ar is substituted with 1 or 2 haloatoms, particularly fluoro atoms.

It is understood that:

represents:

In one particular embodiment, Ar is selected from:

In another particular embodiment, Ar is:

particularly

R¹ is selected from —COOR^(1a), —NHSO₂R^(1b), —SO₂NHR^(1d), —SO₂OH,—C(O)NH—SO₂R^(1c), —P(O)(OH)₂, —CN, —O—CH(R^(1e))—COOH, tetrazol-5-yl,

The R^(1a) moiety is H, —C₁₋₆alkyl, —C₁₋₃alkylenearyl,—C₁₋₃alkyleneheteroaryl, —C₃₋₇cycloalkyl, —CH(C₁₋₄alkyl)OC(O)R^(1aa),—C₀₋₆alkylenemorpholine,

R^(1aa) is —O—C₁₋₆alkyl, —O—C₃₋₇cycloalkyl, —NR^(1ab)R^(1ac), or—CH(NH₂)CH₂COOCH₃. R^(1ab) and R^(1ac) are independently selected fromH, —C₁₋₆alkyl, and benzyl, or are taken together as —(CH₂)₃₋₆—.

The R^(1b) moiety is R^(1c) or —NHC(O)R^(1c). The R^(1c) group is—C₁₋₆alkyl, —C₀₋₆alkylene-O—R^(1ca), —C₁₋₅alkylene-NR^(1cb)R^(1cc), or—C₀₋₄alkylenearyl. The R^(1ca) moiety is H, —C₁₋₆alkyl, orC₁₋₆alkylene-O—C₁₋₆alkyl. The R^(1cb) and R^(1cc) groups areindependently selected from H and —C₁₋₆alkyl, or are taken together as—(CH₂)₂—O—(CH₂)₂— or —(CH₂)₂—N[C(O)CH₃]—(CH₂)₂—. The R^(1d) moiety is H,R^(1c), —C(O)R^(1c), or —C(O)NHR^(1c). The R^(1e) group is C₁₋₄alkyl oraryl.

Each alkyl and each aryl in R¹ is optionally substituted with 1 to 7fluoro atoms. In addition, the term “alkyl” is intended to includedivalent alkylene groups such as those present in —Cl₁₋₃alkylenearyl and—C₁₋₃alkyleneheteroaryl, for example. Further, each aryl and heteroarylgroup that might be present in R¹, may be substituted with 1 to 3 —OH,—C₁₋₆alkyl, —C₂₋₄alkenyl, —C₂₋₄alkynyl, —CN, halo, —O—C₁₋₆alkyl,—S—C₁₋₆allyl, —S(O)—C₁₋₆alkyl, —S(O)₂—C₁₋₄alkyl, -phenyl, —NO₂, —NH₂,—NH—C₁₋₆alkyl, or —N(C₁₋₆alkyl)₂ groups. Further, each of theaforementioned alkyl, alkenyl and alkynyl groups may be substituted with1 to 5 fluoro atoms. It is understood that when referring to “eachalkyl,” “each aryl” and “each heteroaryl” group in R¹, the terms alsoinclude any alkyl, aryl and heteroaryl groups that might be present inthe R^(1a) through R^(1e) moieties.

In one embodiment, R¹ is —COOR^(1a) and R^(1a) is H. In anotherembodiment, R¹ is —COOR^(1a) and R^(1a) is —C₁₋₆alkyl, examples of whichinclude —CH₃, —CH₂CH₃, —(CH₂)₂CH₃, —(CH₂)₂—CF₃, —CH₂CH(CH₃)₂, —CH(CH₃)₂,—CH(CH₃)—CF₃, —CH(CH₂F)₂, —C(CH₃)₃, —(CH₂)₃CH₃, and —(CH₂)₂—CF₂CF₃.Thus, examples of R¹ include —C(O)OCH₃, —COOCH₂CH₃, and so forth.

In one embodiment, R¹ is —COOR^(1a) and R^(1a) is —C₁₋₃alkylenearyl, forexample, a benzyl group, which may be substituted such as chlorobenzyl,fluorobenzyl, difluorobenzyl, -benzyl-CH₃, -benzyl-CF₃, and-benzyl-O—CF₃. Thus, examples of R¹ include: —C(O)OCH₂-benzyl,

In one embodiment, R¹ is —COOR^(1a) and R^(1a) is—C₁₋₃alkyleneheteroaryl, examples of which include —CH₂-pyridinyl. Inone embodiment, R¹ is —COOR^(1a) and R^(1a) is —C₃₋₇cycloalkyl, examplesof which include cyclopentyl.

In yet another embodiment R¹ is —COOR^(1a) and R^(1a) is—CH(C₁₋₄alkyl)OC(O)R^(1aa), where R^(1aa) is —O—C₁₋₆alkyl,—O—C₃₋₇cycloalkyl, —NR^(1ab)R^(1ac) or —CH(NH₂)CH₂COOCH₃. R^(1ab) andR^(1ac) are independently selected from H, —C₁₋₆alkyl, and benzyl, orare taken together as —(CH₂)₃₋₆—. Examples of —O—C₁₋₆alkyl groupsinclude —O—CH₂CH₃ and —O—CH(CH₃)₂. Exemplary —O—C₃₋₇cycloalkyl groupsinclude —O-cyclohexyl. Thus, examples of R¹ includeC(O)OCH(CH₃)OC(O)—O—CH₂CH₃, —C(O)OCH(CH₃)OC(O)—O—CH(CH₃)₂, and—C(O)OCH(CH₃)OC(O)—O-cyclohexyl.

In one embodiment, R¹ is —COOR^(1a) and R^(1a) is—C₀₋₆alkylenemorpholine, examples of which include —(CH₂)₂-morpholineand —(CH₂)₃-morpholine. In another embodiment, R^(1a) is

In one embodiment, R¹ is —NHSO₂R^(1b) and R^(1b) is R^(1c). The R^(1c)group is —C₁₋₆alkyl, —C₀₋₆alkylene-O—R^(1ca),—C₁₋₅alkylene-NR^(1cb)R^(1cc), —C₀₋₄alkylenearyl or—C₀₋₄alkyleneheteroaryl. The R^(1ca) moiety is H, —C₁₋₆alkyl, or—C₁₋₆alkylene-O—C₁₋₆alkyl. The R^(1cb) and R^(1cc) groups areindependently selected from H and —C₁₋₆alkyl, or are taken together as—(CH₂)₂—O—(CH₂)₂— or —(CH₂)₂—N[C(O)CH₃]—(CH₂)₂—. In one embodiment,R^(1c) c is —C₁₋₆alkyl, such that exemplary R¹ groups include —NHSO₂—CH₃and the fluoro-substituted group, —NHSO₂—CF₃. In another embodiment,R^(1c) is —C₀₋₄alkylenearyl, such that exemplary R¹ groups include—NHSO₂-phenyl. In another embodiment, R^(1c) is —C₀₋₄alkyleneheteroaryl,such that exemplary R¹ groups include —NHSO₂-4,5-dimethylisoxazol-3-yl.

In another embodiment, R¹ is —NHSO₂R^(1b) and R^(1b) is —NHC(O)R^(1c),where R^(1c) is defined above. In a particular embodiment, R¹ is—NHSO₂R^(1b), R^(1b) is —NHC(O)R^(1c), and R^(1c) is —C₁₋₆alkyl or—C₀₋₄alkylenearyl.

In one embodiment, R¹ is —SO₂NHR^(1d) and R^(1d) is H. In anotherembodiment, R¹ is —SO₂NHR^(1d) and R^(1d) is R^(1c), where R^(1c) isdefined above. In a particular embodiment, R^(1c) is —C₁₋₆alkyl or—C₀₋₄alkylenearyl. When R^(1c) is —C₁₋₆alkyl, exemplary R¹ groupsinclude the fluoro-substituted groups —SO₂NH—CF₃, —SO₂NH—CHF₂,—SO₂NH—CF₂CH₂F and —SO₂NH—CF₂CF₂CF₃.

In another embodiment, R¹ is —SO₂NHR^(1d) and R^(1d) is —C(O)R^(1c),where R^(1c) is defined above. In one embodiment of particular interest,R^(1c) is —C₁₋₆alkyl or —C₀₋₄alkylenearyl. When R^(1c) is —C₁₋₆alkyl,exemplary R¹ groups include —SO₂NHC(O)CH₃ and —SO₂NHC(O)—(CH₂)₂CH₃. WhenR^(1c) is —C₀₋₆alkylene-O—R^(1ca) and R^(1ca) is H, exemplary R¹ groupsinclude —SO₂NHC(O)CH₂OH, —SO₂NHC(O)CH(CH₃)OH, and —SO₂NHC(O)C(CH₃)₂OH.When R^(1c) is —C₀₋₆alkylene-O—R^(1ca) and R^(1ca) is —C₁₋₆alkyl,exemplary R¹ groups include —SO₂NHC(O)CH₂—O—CH₃, —SO₂NHC(O)—O—CH₃, and—SO₂NHC(O)—O—CH₂CH₃. When R^(1c) is —C₀₋₆alkylene-O—R^(1ca) and R^(1ca)is —C₁₋₆alkylene-O—C₁₋₆alkyl, exemplary R¹ groups include—SO₂NHC(O)CH₂—O—(CH₂)₂—O—CH₃. When R^(1c) is—C₁₋₅alkylene-NR^(1cb)R^(1cc), exemplary R¹ groups include—SO₂NHC(O)CH₂N(CH₃)₂, —SO₂NHC(O)—CH₂—NH₂, and —SO₂NHC(O)—CH(CH₃)—NH₂.Another example when R^(1c) is —C₁₋₅alkylene-NR^(1cb)R^(1cc) is wherethe R^(1cb) and R^(1cc) are taken together as —(CH₂)₂—O—(CH₂)₂— or—(CH₂)₂—N[C(O)CH₃]—(CH₂)₂—. Such exemplary R¹ groups include:

In another embodiment, R¹ is —SO₂NHR^(1d) and R^(1d) is —C(O)NHR^(1c),where R^(1c) is defined above. In a particular embodiment, R^(1c) is—C₁₋₆alkyl or —C₀₋₄alkylenearyl. When R^(1c) is —C₁₋₆alkyl, exemplary R¹groups include —SO₂NHC(O)NH—CH₂CH₃ and —SO₂NHC(O)NH—(CH₂)₂CH₃. WhenR^(1c) is —C₀₋₄alkylenearyl, exemplary R¹ groups include—SO₂NHC(O)NH-phenyl.

In another embodiment, R¹ is —SO₂OH, and in still another embodiment, R¹is —P(O)(OH)₂. In yet another embodiment, R¹ is —CN.

In another embodiment, R¹ is —C(O)NH—SO₂R^(1c), where R^(1c) is definedabove. In a particular embodiment, R^(1c) is —C₁₋₆alkyl or—C₀₋₄alkylenearyl. When R^(1c) is —C₁₋₆alkyl, exemplary R¹ groupsinclude —C(O)—NH—SO₂—CH₃, —C(O)—NH—SO₂—CH₂CH₃ and the fluoro-substituted—C(O)—NH—SO₂—CF₃ group.

In another embodiment, R¹ is —O—CH(R^(1e))—COOH, where R^(1e) is—C₁₋₄alkyl or aryl. Examples of such R¹ groups include, —O—CH(CH₃)—COOHand —O—CH(phenyl)-COOH.

In an embodiment of particular interest, R¹ is tetrazol-5-yl. In anotherembodiment, R¹ is:

R² is selected from H, halo, —NO₂, —C₁₋₆alkyl, —C₂₋₆alkenyl,—C₃₋₆cycloalkyl, —CN, —C(O)R^(2a), —C₀₋₅alkylene-OR^(2b),—C₀₋₅alkylene-NR^(2c)R^(2d), —C₀₋₃alkylenearyl, and—C₀₋₃alkyleneheteroaryl. In one particular embodiment, R² is selectedfrom H, —C₀₋₅alkylene-OR^(2b), and halo; and in another embodiment, R²is selected from H and halo. In one embodiment R² is halo such as chloroor fluoro. In another embodiment R² is C₁₋₆alkyl such as —CH₃ and—CH₂CH₃. In yet another embodiment R² is —C₀₋₃alkylenearyl, such asphenyl. In one embodiment, R² is —C(O)R^(2a). The R^(2a) substituent canbe H, —C₁₋₆alkyl, —C₃₋₆cycloalkyl, —OR^(2b) or —NR^(2c)R^(2d). R^(2b) isselected from H, —C₁₋₆alkyl, —C₃₋₆cycloalkyl, and —C₀₋₁alkylenearyl. TheR^(2c) and R^(2d) groups are independently selected from H, —C₁₋₄alkyl,and —C₀₋₁alkylenearyl. In another particular embodiment, R² is—C₀₋₅alkylene-OR^(2b), more particularly —C₀₋₃alkylene-OR^(2b). Inexemplary embodiments, and R^(2b) is H or —C₁₋₆alkyl, for example R² canbe —CH₂OH, —C(CH₃)₂OH or —OCH₃.

Each alkyl and each aryl in R² is optionally substituted with 1 to 7fluoro atoms. It is understood that when referring to the “alkyl” in R²,the term includes any alkyl groups that might be present in the R^(2a),R^(2b), R^(2c) and R^(2d) moieties. In addition, the aryl and heteroarylin R², for example in —C₀₋₃alkylenearyl or —C₀₋₃alkyleneheteroaryl, maybe substituted with 1 to 3 —OH, —C₁₋₆alkyl, —C₂₋₄alkenyl, —C₂₋₄alkynyl,—CN, halo, —O—C₁₋₆alkyl, —S—C₁₋₆alkyl, —S(O)₂—C₁₋₄alkyl, -phenyl, —NO₂,—NH₂, —NH—C₁₋₆alkyl, or —N(C₁₋₆alkyl)₂ groups. Further, each of theaforementioned alkyl, alkenyl and alkynyl groups may be substituted with1 to 5 fluoro atoms. It is understood that when referring to the “aryl”or “heteroaryl” in R², the term includes any aryl and heteroaryl groupsthat might be present in the R^(2a), R^(2b), R^(2c) and R^(2d) moieties.

R³ is selected from —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₃₋₁₀alkynyl,—C₀₋₃alkylene-C₃₋₇cycloalkyl, —C₂₋₃alkenylene-C₃₋₇cycloalkyl,—C₂₋₃alkynylene-C₃₋₇cycloalkyl,—C₀₋₅alkylene-NR^(3a)—C₀₋₅alkylene-R^(3b),—C₀₋₅alkylene-O—C₀₋₅alkylene-R^(3b),—C₀₋₅alkylene-S—C₁₋₅alkylene-R^(3b), and —C₀₋₃alkylenearyl. The R^(3a)group is H, —C₁₋₆alkyl, —C₃₋₇cycloalkyl, or —C₀₋₃alkylenearyl (forexample, —C₀₋₁alkylenearyl such as phenyl and benzyl). The R^(3b) groupis H, —C₁₋₆alkyl, —C₃₋₇cycloalkyl, —C₂₋₄alkenyl, —C₂₋₄alkynyl, or aryl(such as phenyl).

In addition, each alkyl and each aryl in R³ is optionally substitutedwith 1 to 7 fluoro atoms, where the term “alkyl” is intended to includedivalent alkylene groups such as those present in—C₀₋₃alkylene-C₃₋₇cycloalkyl and —C₀₋₃alkylenearyl, for example. Eacharyl in R³, for example in —C₀₋₃alkylenearyl or aryl, may be substitutedwith 1 to 3 —OH, —C₁₋₆alkyl, —C₂₋₄alkenyl, —C₂₋₄alkynyl, —CN, halo,—O—C₁₋₆alkyl, —S—C₁₋₆alkyl, —S(O)—C₁₋₆alkyl, —S(O)₂—C₁₋₄alkyl, -phenyl,—NO₂, —NH₂, —NH—C₁₋₆allyl, or —N(C₁₋₆alkyl)₂ groups. Further, each ofthe aforementioned alkyl, alkenyl and alkynyl groups may be substitutedwith 1 to 5 fluoro atoms. It is understood that when referring to “eachalkyl” and “each aryl” group in R³, the terms also include any alkyl andaryl groups that might be present in the R^(3a) and R^(3b) moieties.

In one embodiment, R³ is —C₁₋₁₀alkyl optionally substituted with 1 to 7fluoro atoms such as —CF₃. In another embodiment, R³ is —C₂₋₇allyl; andin yet another embodiment, R³ is —C₂₋₅alkyl, examples of which include,—CH₂CH₃, —(CH₂)₂CH₃, and —(CH₂)₃CH₃.

In another embodiment, R³ is —C₂₋₁₀alkenyl such as —CH₂CH═CHCH₃. In yetanother embodiment, R³ is —C₃₋₁₀alkynyl such as —CH₂C≡CCH₃.

In another embodiment, R³ is —C₀₋₃alkylene-C₃₋₇cycloalkyl such as-cyclopropyl, —CH₂-cyclopropyl, cyclopentyl, —CH₂-cyclopentyl,—(CH₂)₂-cyclopentyl, and —CH₂-cyclohexyl. In a particular embodiment, R³is —C₀₋₁alkylene-C₃₋₅cycloalkyl. In one embodiment, R³ is—C₂₋₃alkenylene-C₃₋₇cycloalkyl such as —CH₂CH═CH-cyclopentyl; and inanother embodiment, R³ is —C₂₋₃alkynylene-C₃₋₇cycloalkyl such as—CH₂C≡C-cyclopentyl.

In yet another embodiment, R³ is—C₀₋₅alkylene-NR^(3a)—C₀₋₅alkylene-R^(3b). In one particular embodiment,R^(3a) is H and R^(3b) is —C₁₋₆alkyl. Examples of such R³ groups include—NHCH₂CH₃, —NHCH(CH₃)₂, —NH(CH₂)₂CH₃, —NH(CH₂)₃CH₃, —NHCH(CH₃)CH₂CH₃,—NH(CH₂)₄CH₃, and —NH(CH₂)₅CH₃.

In one embodiment, R³ is —C₀₋₅alkylene-O—C₀₋₅alkylene-R^(3b). In oneparticular embodiment, R^(3b) is selected from H, —C₁₋₆alkyl and aryl.Examples of such R³ groups include —OCH₃, —OCH₂CH₃, —OCH(CH₃)₂,O(CH₂)₂CH₃, —O(CH₂)₃CH₃, —OCH₂CH(CH₃)₂, —O-phenyl, and —O-benzyl. Inanother embodiment, R³ is —C₀₋₅alkylene-O—C₀₋₅alkylene-R^(3b), whereR^(3b) is —C₁₋₆alkyl, and in another embodiment, R³ is —O—C₁₋₅alkyl.

In another embodiment, R³ is —C₀₋₅alkylene-S—C₁₋₅alkylene-R^(3b), and inone particular embodiment R^(3b) is H, such as when R³ is —CH₂—S—CH₂CH₃.In another embodiment, R³ is —C₀₋₃alkylenearyl, such as phenyl, benzyl,and —(CH₂)₂-phenyl.

In one particular embodiment of interest, R³ is —C₁₋₁₀alkyl or—C₀₋₅alkylene-O—C₀₋₅alkylene-R^(3b), where R^(3b) is H; and in aspecific embodiment, R³ is selected from —C₂₋₅alkyl and—C₁alkylene-O—C₁₋₅alkylene-H.

X is —C₁₋₁₂alkylene-, where at least one —CH₂— moiety in the alkylene isreplaced with a —NR^(4a)—C(O)— or —C(O)—NR^(4a)— moiety. Thus X can be—C₁alkylene-, —C₁alkylene-, —C₂alkylene-, —C₃alkylene-, —C₄alkylene-,—C₅alkylene-, —C₆allylene-, —C₇alkylene-, —C₈alkylene, —C₉alkylene-,—C₁₀alkylene-, —C₁₁alkylene-, and —C₁₋₂alkylene-, with at least one—CH₂— moiety being replaced. R^(4a) is selected from H, —OH, and—C₁₋₄allyl. In one embodiment, R^(4a) is H.

Each carbon atom in the —C₁₋₁₂alkylene-group may be substituted with oneor more R^(4b) groups. R^(4b) is selected from —C₀₋₅alkylene-COOR^(4c),—C₁₋₆alkyl, —C₀₋₁alkylene-CONH₂, —C₁₋₂alkylene-OH,—C₀₋₃alkylene-C₃₋₇cycloalkyl, 1H-indol-3-yl, benzyl, and hydroxybenzyl,where R^(4c) is H or —C₁₋₄alkyl. In one embodiment, the carbon atoms in—C₁₋₁₂alkylene- are unsubstituted with R^(4b) groups. In anotherembodiment, 1 or 2 carbon atoms are substituted with one or two R^(4b)groups. In another embodiment, one carbon atom is substituted with oneR^(4b) group. In one particular embodiment, R^(4b) is —COOH, benzyl, or—C₁₋₆alkyl, including —C₁₋₃alkyl groups such as —CH₃ and —CH(CH₃)₂.

In addition, one —CH₂— moiety in X may be replaced with a group selectedfrom —C₄₋₈cycloalkylene-, —CR^(4d)═CH—, and —CH═CR^(4d)—. R^(4d) isselected from —CH₂-thiophene and phenyl. In one embodiment, none of the—CH₂— moieties are so replaced. In another embodiment, one —CH₂— moietyis replaced with —C₄₋₈cycloalkylene-, for example, cyclohexylene. Inanother embodiment, one —CH₂— moiety is replaced with —CH═CR^(4d)—,where R^(4d) is —CH₂-thiophene such as —CH₂-thiophen-2-yl.

Each alkyl and each aryl in R^(4a), R^(4b), R^(4c), and R^(4d), may besubstituted with 1 to 7 fluoro atoms, and the term “alkyl” is intendedto include divalent alkylene groups such as that present in—C₀₋₅alkylene-COOR^(4c), for example. It is noted that the R^(4b) group,—C₀₋₃alkylene-C₃₋₇cycloalkyl, is intended to include a C₃₋₇cycloalkyllinked to the X —C₁₋₁₂alkylene-chain by a bond as well as aC₃₋₇cycloalkyl that is directly attached to the chain, as illustratedbelow:

In one embodiment, one to four —CH₂— moieties are replaced. In anotherembodiment, one —CH₂— moiety is replaced, examples of which include:—C(O)NH— and —CH₂—NHC(O)—. In one embodiment, X is —C₂₋₁₁alkylene- and1, 2, or 3 —CH₂— moieties are replaced with a —NR^(4a)—C(O)— or—C(O)—NR^(4a)— moiety. In another embodiment, X is —C₂₋₅alkylene-, where1 or 2 —CH₂— moieties are replaced. When more than one —CH₂— moiety inC₁₋₁₂alkylene is replaced with a —NR^(4a)—C(O)— or —C(O)—NR^(4a)—moiety, the replaced moieties may be contiguous or non-contiguous.Exemplary X groups include the following, which depict, examples whereone or more —CH₂— moieties are replaced with —NR^(4a)—C(O)— or—C(O)—NR^(4a)— moieties, examples where —CH₂— moieties are replaced witha group selected from —C₄₋₈cycloalkylene-, —CR^(4d)═CH—, and—CH═CR^(4d)—, as well as examples where carbon atoms in the—C₁₋₁₂alkylene-group are substituted with one or more R^(4b) groups:

C₁alkylene with one —CH₂— moiety replaced:

-   -   —C(O)NH—    -   —NHC(O)—

C₂alkylene with one —CH₂— moiety replaced:

-   -   —CH₂—NHC(O)—    -   —C(O)NH—CH₂—    -   —CH₂—C(O)NH—    -   —CH[CH(CH₃)₂]-C(O)NH—

C₂alkylene with two —CH₂— moieties replaced:

-   -   —C(O)NH—NHC(O)—    -   —CH═C(—CH₂-2-thiophene)-C(O)NH—

C₃alkylene with one —CH₂— moiety replaced:

-   -   —(CH₂)₂—NHC(O)—    -   —CH(CH₃)—CH₂—NHC(O)—    -   —CH[CH(CH₃)₂]-CH₂—NHC(O)—    -   —CH(COOH)—CH₂—NHC(O)—    -   —CH₂—CH(COOH)—NHC(O)—

C₃alkylene with two —CH₂— moieties replaced:

-   -   —NHC(O)—CH₂—NHC(O)—

C₄alkylene with one —CH₂— moiety replaced:

-   -   —(CH₂)₃—NHC(O)—    -   —C(O)NH—CH₂—CH(COOH)—CH₂—

C₄alkylene with two —CH₂— moieties replaced:

-   -   —C(O)NH—CH(benzyl)-CH₂—NHC(O)—    -   —C(O)NH—CH(benzyl)-CH₂—C(O)NH—    -   —CH₂—NHC(O)—CH₂—NHC(O)—

C₄alkylene with three —CH₂— moieties replaced:

-   -   —CH₂—NHC(O)-cyclohexylene-NHC(O)—    -   —CH₂—N(OH)C(O)-cyclohexylene-NHC(O)—

C₅alkylene with two —CH₂— moieties replaced:

-   -   —CH₂—NHC(O)—CH₂—CH(COOH)—NHC(O)—    -   —CH₂—NHC(O)—(CH₂)₂—NHC(O)—    -   —C(O)NH—(CH₂)₂—C(O)N(OH)—CH₂—    -   —C(O)NH—(CH₂)₂—CH(COOH)—NHC(O)—    -   —CH(COOH)—CH₂—NHC(O)—CH₂—NHC(O)—    -   —(CH₂)₂—NHC(O)-cyclohexylene-NHC(O)—

C₆alkylene with two —CH₂— moieties replaced:

-   -   —C(O)NH—(CH₂)₄—NHC(O)—    -   —CH₂—NHC(O)—(CH₂)₂—CH(COOH)—NHC(O)—    -   —C(O)NH—(CH₂)₃—CH(COOH)—NHC(O)—

C₆alkylene with three —CH₂— moieties replaced:

-   -   —C(O)NH—(CH₂)₂—NHC(O)—CH₂—NHC(O)—

C₆alkylene with four —CH₂— moieties replaced:

-   -   —C(O)NH—(CH₂)₂—NHC(O)-cyclohexylene-NHC(O)—

C₇alkylene with two —CH₂— moieties replaced:

-   -   —CH₂—NHC(O)—(CH₂)₄—NHC(O)—    -   —C(O)NH—(CH₂)₄—CH(COOH)—NHC(O)—

C₇alkylene with three —CH₂— moieties replaced:

-   -   —CH[CH(CH₃)₂]-C(O)NH—(CH₂)₂—NHC(O)—CH₂—NHC(O)—

C₇alkylene with four —CH₂— moieties replaced:

-   -   —CH₂—NHC(O)—(CH₂)₂—NHC(O)-cyclohexylene-NHC(O)—    -   —CH₂—C(O)NH—(CH₂)₂—NHC(O)-cyclohexylene-NHC(O)—

C₈alkylene with three —CH₂— moieties replaced:

-   -   —C(O)NH—(CH₂)₄—NHC(O)—CH₂—NHC(O)—

C₈alkylene with four —CH₂— moieties replaced:

-   -   —C(O)NH—(CH₂)₄—NHC(O)-cyclohexylene-NHC(O)—

C₉alkylene with two —CH₂— moieties replaced:

-   -   —CH₂—NHC(O)—(CH₂)₆—NHC(O)—

C₉alkylene with four —CH₂— moieties replaced:

-   -   —CH₂—NHC(O)—(CH₂)₄—NHC(O)-cyclohexylene-NHC(O)—

C₁₀alkylene with four —CH₂— moieties replaced:

-   -   —C(O)NH—(CH₂)₆—NHC(O)-cyclohexylene-NHC(O)—

C₁₁alkylene with three —CH₂— moieties replaced:

-   -   —CH(CH(CH₃)₂)—C(O)NH—(CH₂)₆—NHC(O)—CH₂—NHC(O)—

C₁₁alkylene with four —CH₂— moieties replaced:

-   -   —CH₂—NHC(O)—(CH₂)₆—NHC(O)-cyclohexylene-NHC(O)—        In one particular embodiment, X is —C(O)NH— or —CH₂—NHC(O)—.

R⁵ is selected from —C₀₋₃alkylene-SR^(5a),—C₀₋₃alkylene-C(O)NR^(5b)R^(5c), —C₀₋₃alkylene-NR^(5b)—C(O)R^(5d),—NH—C₀₋₁alkylene-P(O)(OR^(5e))₂, —C₀₋₃alkylene-P(O)OR^(5e)R^(5f),—C₀₋₂alkylene-CHR⁵⁹—COOH, —C₀₋₃alkylene-C(O)NR^(5h)—CHR^(5i)—COON, and—C₀₋₃alkylene-S—SR^(5j). Each alkyl and each aryl in R⁵ is optionallysubstituted with 1 to 7 fluoro atoms, where the term “alkyl” is intendedto include divalent alkylene groups such as those present in—C₀₋₃alkylene-SR^(5a) and —C₀₋₃alkylene-P(O)OR^(5e)R^(5f), for example.Each aryl and heteroaryl in R⁵ may be substituted with 1 to 3 —OH,—C₁₋₆alkyl, —C₂₋₄alkenyl, —C₂₋₄alkynyl, —CN, halo, —O—C₁₋₆alkyl,—S—C₁₋₆alkyl, —S(O)—C₁₋₆alkyl, —S(O)₂—C₁₋₄alkyl, -phenyl, —NO₂, —NH₂,—NH—C₁₋₆alkyl, or —N(C₁₋₆alkyl)₂ groups. Further, each of theaforementioned alkyl, alkenyl and alkynyl groups may be substituted with1 to 5 fluoro atoms. It is understood that when referring to “eachalkyl,” “each aryl” and “each heteroaryl” group in R⁵, the terms alsoinclude any alkyl, aryl and heteroaryl groups that might be present inthe R^(5a-5j), R^(5aa), R^(5ab), R^(5ba), R^(5bb), R^(5bc), R^(5ca),R^(5da), R^(5db), R^(5ea), R^(5eb), R^(5ec), R^(5fa), and R^(5fb)moieties.

In one embodiment, R⁵ is —C₀₋₃alkylene-SR^(5a). R^(5a) is H or—C(O)—R^(5aa). The R^(5aa) group is —C₁₋₆alkyl,—C₀₋₆alkylene-C₃₋₇cycloalkyl, —C₀₋₆alkylenearyl,—C₀₋₆alkyleneheteroaryl, —C₀₋₆alkylenemorpholine,—C₀₋₆alkylenepiperazine-CH₃, —CH[N(R^(5ab))₂]-aa where aa is an aminoacid side chain, -2-pyrrolidine, —C₀₋₆alkylene-OR^(5ab),—O—C₀₋₆alkylenearyl, —C₁₋₂alkylene-OC(O)—C₁₋₆alkyl,—C₁₋₂alkylene-OC(O)—C₀₋₆alkylenearyl, or—O—C₁₋₂alkylene-OC(O)O—C₁₋₆alkyl. The R^(5ab) group is H or —C₁₋₆alkyl.In one specific embodiment, R^(5a) is H, for example, R⁵ may be —SH or—CH₂SH. In another embodiment, R^(5a) is —C(O)—R^(5aa), where R^(5aa) is—C₁₋₆alkyl. Exemplary —C₁₋₆alkyl groups include —CH₃, —CH₂CH₃,—CH(CH₃)₂, —C(CH₃)₃, and —CH₂CH(CH₃)₂. Thus, examples of R⁵ include—SC(O)CH₃, —CH₂SC(O)CH₃, —CH₂SC(O)CH₂CH₃, —CH₂SC(O)CH(CH₃)₂ and—CH₂SC(O)C(CH₃)₃, and —CH₂SC(O)CH₂CH(CH₃)₂. In one embodiment, R^(5a) isselected from H and —C(O)—C₁₋₆alkyl.

In one embodiment, R^(5a) is —C(O)—R^(5aa), where R^(5aa) is—C₀₋₆alkylene —C₃₋₇cycloalkyl. Exemplary C₃₋₇cycloalkyl groups includecyclopentyl and cyclohexyl. Thus, examples of R⁵ include—CH₂SC(O)-cyclopentyl, —CH₂SC(O)-cyclohexyl, and—CH₂SC(O)—CH₂-cyclopentyl. In another embodiment, R^(5a) is—C(O)—R^(5aa), where R^(5aa) is —C₀₋₆alkylenearyl. In one specificembodiment, the aryl is optionally substituted with 1 to 3 substituentssuch as —O—C₁₋₆alkyl. Exemplary aryl groups include phenyl and-phenyl-OCH₃. Thus, examples of R⁵ include —CH₂SC(O)-phenyl and—CH₂SC(O)-phenyl-OCH₃.

In yet another embodiment, R^(5a) is —C(O)—R^(5aa), where R^(5aa) is—C₀₋₆alkyleneheteroaryl. Exemplary heteroaryl groups include furanyl,thienyl and pyridinyl. Thus, examples of R⁵ include:—CH₂SC(O)-2-pyridine, —CH₂SC(O)-3-pyridine, and —CH₂SC(O)-4-pyridine. Inanother embodiment, R^(5a) is —C(O)—R^(5aa), where R^(5aa) is—C₀₋₆alkylenemorpholine:

more particularly, —C₁₋₃alkylenemorpholine. Thus, examples of R⁵ include—CH₂S—C(O)CH₂-morpholine and —CH₂S—C(O)(CH₂)₂-morpholine. In anotherembodiment, R^(5a) is —C(O)—R^(5aa), where R^(5aa) is—C₀₋₆alkylenepiperazine-CH₃. Thus, examples of R⁵ include—CH₂S—C(O)(CH₂)₂-piperazine-CH₃. In one embodiment, R^(5a) is—C(O)—R^(5aa), where R^(5aa) is —CH[N(R^(5ab))₂]-aa where aa is an aminoacid side chain. For example, the amino acid side chain could be—CH(CH₃)₂, the valine side chain. Thus, one example of R⁵ is—CH₂S—C(O)CH(NH₂)—CH(CH₃)₂. In yet another embodiment, R^(5a) is—C(O)—R^(5aa), where R^(5aa) is −2-pyrrolidine:

Thus, an example of R⁵ is —CH₂S—C(O)-2-pyrrolidine.

In another embodiment, R^(5a) is —C(O)—R^(5aa), where R^(5aa) is—C₀₋₆alkylene-OR^(5ab). In one embodiment, R^(5ab) is H, such thatR^(5a) is —C(O)—C₀₋₆alkylene-OH. In another embodiment, R^(5ab) is—C₁₋₆alkyl, such that R^(5a) is —C(O)—C₀₋₆alkylene-O—C₁₋₆alkyl, forexample, R⁵ may be —CH₂SC(O)—O—CH₂CH₃.

In another embodiment, R^(5a) is —C(O)—R^(5aa), where R^(5aa) is—O—C₀₋₆alkylenearyl. In yet another embodiment, R^(5a) is —C(O)—R^(5aa),where R^(5aa) is —C₁₋₂alkylene-OC(O)—C₁₋₆alkyl and in anotherembodiment, R^(5a) is —C(O)—R^(5aa), where R^(5aa) is—C₁₋₂alkylene-OC(O)—C₀₋₆alkylenearyl. In yet another embodiment, R^(5a)is —C(O)—R^(5aa), where R^(5aa) is —O—C₁₋₂alkylene-OC(O)O—C₁₋₆alkyl, forexample, R⁵ may be —CH₂SC(O)OCH(CH₃)—OC(O)O—CH(CH₃)₂.

In one embodiment, R⁵ is —C₀₋₃alkylene-C(O)NR^(5b)R^(5c). The R^(5b)moiety is H, —OH, —OC(O)R^(5ba), —CH₂COOH, —O-benzyl, -pyridyl, or—OC(S)NR^(5bb)R^(5bc). R^(5ba) is H, —C₁₋₆alkyl, aryl, —OCH₂-aryl (forexample, —OCH₂-phenyl), —CH₂O-aryl (for example, —CH₂O-phenyl), or—NR^(5bb)R^(5bc). The R^(5bb) and R^(5bc) moieties are independentlyselected from H and —C₁₋₄alkyl. In one embodiment, R^(5b) is —OH or—OC(O)R^(5ba), where —R^(5ba) is —C₁₋₆allyl. R⁵ is H, —C₁₋₆alkyl, or—C(O)—R^(5ca). R^(5ca) is H, —C₁₋₆alkyl, —C₃₋₇cycloalkyl, aryl, orheteroaryl. In one particular embodiment, R^(5c) is H. In anotherembodiment, R^(5b) is —OH and R^(5c) is H, for example, R⁵ may be—C(O)NH(OH) or —CH₂C(O)NH(OH). In another embodiment, R^(5b) is—OC(O)R^(5ba), where —R^(5ba) is —C₁₋₆alkyl, and R^(5c) is H, forexample, R⁵ may be —C(O)N[OC(O)CH₃]H or —C(O)N[OC(O)C(CH₃)₃]H. In stillanother embodiment, both R^(5b) and R^(5c) are H, for example, R⁵ may be—C(O)NH₂. In another embodiment, R^(5b) is —CH₂COOH and R^(5c) is H, forexample, R⁵ may be —C(O)N(CH₂COOH)H. In yet another embodiment, R^(5b)is —OC(O)R^(5ba), where —R^(5ba) is —O—CH₂-aryl or —CH₂—O-aryl, forexample, R^(5b) may be —OC(O)OCH₂-phenyl or —OC(O)CH₂—O-phenyl, andR^(5C) is H. Therefore, examples of R⁵ include—CH₂—C(O)NH[OC(O)OCH₂-phenyl] and —CH₂—C(O)N[OC(O)—CH₂O-phenyl]H. Inanother embodiment, R^(5b) is —OC(S)NR^(5bb)R^(5bc), where R^(5bb) andR^(5bc) are both —C₁₋₄alkyl, for example, R^(5b) may be —O—C(S)N(CH₃)₂.In another embodiment, R^(5b) is —OC(S)NR^(5bb)R^(5bc) and R^(5c) is H,for example, R⁵ may be —CH₂—C(O)N[OC(S)N(CH₃)₂]H.

In one embodiment, R⁵ is —C₀₋₃alkylene-NR^(5b)—C(O)R^(5d). R^(5d) is H,—C₁₋₄alkyl, —C₀₋₃alkylenearyl, —NR^(5da)R^(5db), —CH₂SH, or—O—C₁₋₆allyl. The R^(5da) and R^(5db) moieties are independentlyselected from H and —C₁₋₄alkyl. In another embodiment, R^(5b) is —OH andR^(5d) is H, for example, R⁵ may be —CH₂—N(OH)C(O)H. In anotherembodiment, R^(5b) is —OH and R^(5d) is —C₁₋₄alkyl, for example, R⁵ maybe —CH₂—N(OH)C(O)CH₃. In another embodiment, R^(5b) is H and R^(5d) is—CH₂SH, for example, R⁵ may be —NHC(O)CH₂SH or —CH₂NHC(O)—CH₂SH.

In yet another embodiment, R⁵ is —NH—C₀₋₁alkylene-P(O)(OR^(5e))₂. TheR^(5e) moiety is H, —C₁₋₆alkyl, —C₁₋₃alkylenearyl,—C₁₋₃alkyleneheteroaryl, —C₃₋₇cycloalkyl, —CH(CH₃)—O—C(O)R^(5ea),

The R^(5ea) group is —O—C₁₋₆alkyl, —O—C₃₋₇cycloalkyl, —NR^(5eb)R^(5ec),or —CH(NH₂)CH₂COOCH₃. R^(5eb) and R^(5ec) are independently selectedfrom H, —C₁₋₄alkyl, and —C₁₋₃alkylenearyl (for example, benzyl). R^(5eb)and R^(5ec) may also be taken together to form —(CH₂)₃₋₆—. In oneembodiment, R^(5e) is H, for example, R⁵ may be —NH—CH₂—P(O)(OH)₂.

In one embodiment, R⁵ is —C₀₋₃alkylene-P(O)OR^(5e)R^(5f). The R^(5f)moiety is H, C₁₋₄alkyl, —C₀₋₃alkylenearyl,—C₁₋₃alkylene-NR^(5fa)R^(5fb), or—C₁₋₃alkylene(aryl)-C₀₋₃alkylene-NR^(5fa)R^(5fb). The R^(5fa) andR^(5fb) groups are independently selected from H and —C₁₋₄alkyl. In oneembodiment, R^(5c) is H, for example, R⁵ may be—C₀₋₃alkylene-P(O)(OH)R^(5f).

In one embodiment, R⁵ is —C₀₋₂alkylene-CHR^(5g)—COOH. The R^(5g) moietyis H, —C₁₋₆alkyl, —C₁₋₃alkylenearyl, or —CH₂—O—(CH₂)₂—OCH₃. In oneembodiment, R^(5g) is —CH₂—O—(CH₂)₂—OCH₃, for example, R⁵ may be—CH₂—C[CH₂—O—(CH₂)₂—OCH₃]H—COOH. In another embodiment, R^(5g) is H, forexample, R⁵ may be —CH₂COOH.

In one embodiment, R⁵ is —C₀₋₃alkylene-C(O)NR^(5h)—CHR^(5i)—COOH. TheR^(5h) moiety is H or —C₁₋₄alkyl. The R^(5i) moiety is H, —C₁₋₄alkyl, or—C₀₋₃alkylenearyl. In one embodiment, R^(5h) is H and R^(5i) is—C₀₋₃alkylenearyl, and the aryl is optionally substituted with 1 to 3substituents such as —OH, for example, R⁵ may be—C(O)NH—CH(CH₂-phenyl-OH)(COOH).

In another embodiment, R⁵ is —C₀₋₃alkylene-S—SR^(5j), and R^(5j) isselected from —C₁₋₆alkyl, aryl, and —CH₂CH(NH₂)COOH. Examples of such R⁵groups include —C₀₋₃alkylene-S—S—CH₃, —C₀₋₃alkylene-S—S-phenyl, and—C₀₋₃alkylene-S—S—CH₂CH(NH₂)—COOH.

R⁶ is selected from —C₁₋₆alkyl, —CH₂—O—(CH₂)₂OCH₃, —C₀₋₃alkylenearyl,—C₀₋₃alkyleneheteroaryl, and —C₀₋₃alkylene-C₃₋₇cycloalkyl. In oneparticular embodiment, R⁶ is selected from —C₁₋₆alkyl,—C₀₋₃alkylenearyl, and —C₀₋₃alkylene-C₃₋₇cycloalkyl. Each alkyl and eacharyl in R⁶ is optionally substituted with 1 to 7 fluoro atoms, where theterm “alkyl” is intended to include divalent alkylene groups such asthose present in —C₁₋₆alkylene-O—C₁₋₆alkyl and—C₀₋₃allylene-C₃₋₇cycloalkyl, for example. In addition, each aryl andheteroaryl in R⁶ may be substituted with 1 to 3 —OH, —C₁₋₆alkyl,—C₂₋₄alkenyl, —C₂₋₄alkynyl, —CN, halo, —O—C₁₋₆alkyl, —S—C₁₋₆alkyl,—S(O)—C₁₋₆alkyl, —S(O)₂—C₁₋₄alkyl, -phenyl, —NO₂, —NH₂, —NH—C₁₋₆alkyl,or —N(C₁₋₆alkyl)₂ groups. Further, each of the aforementioned alkyl,alkenyl and alkynyl groups may be substituted with 1 to 5 fluoro atoms.

In one embodiment, R⁶ is —C₁₋₆alkyl, for example, —CH₃, —CH₂CH₃,—CH(CH₃)₂, —(CH₂)₂CH₃, —(CH₂)₃CH₃, —CH(CH₃)CH₂CH₃, —CH₂CH(CH₃)₂,—CH₂C(CH₃)₃, —(CH₂)₂CH(CH₃)₂, or —(CH₂)₄—CH₃. As noted above, each alkylin R⁶ is optionally substituted with 1 to 7 fluoro atoms. Examples ofsuch fluoro-substituted R⁶ groups include —(CH₂)₂CF₃ and —(CH₂)₃CF₃.

In another embodiment, R⁶ is —CH₂—O—(CH₂)₂OCH₃. In still another oneembodiment, R⁶ is —C₁₋₆alkylene-O—C₁₋₆alkyl, for example, —OCH₃ and—CH₂OCH₃.

In one embodiment, R⁶ is —C₀₋₃alkylenearyl, for example, phenyl, benzyl,—CH₂-biphenyl, —(CH₂)₂-phenyl and —CH₂-naphthalen-1-yl. The aryl may besubstituted with 1 to 3 substituents. Thus, other examples of R⁶ includemono-substituted groups such as, methylbenzyl, chlorobenzyl,fluorobenzyl, fluorophenyl, bromobenzyl, iodobenzyl, -benzyl-CF₃,2-trifluoromethyl-benzyl, -benzyl-CN, and -benzyl-NO₂; anddi-substituted groups such as di-chlorobenzyl and di-fluorobenzyl. Eacharyl may also be substituted with 1 to 7 fluoro atoms. Thus, otherexamples of R⁶ include penta-fluorobenzyl.

In one embodiment, R⁶ is —C₀₋₃alkyleneheteroaryl, for example,—CH₂-pyridyl, —CH₂-furanyl, —CH₂-thienyl, and —CH₂-thiophenyl. Inanother embodiment, R⁶ is —C₀₋₃alkylene-C₃₋₇cycloalkyl, for example,—CH₂-cyclopropyl, cyclopentyl, —CH₂-cyclopentyl, -cyclohexyl, and—CH₂-cyclohexyl.

R⁷ is H or is taken together with R⁶ to form —C₃₋₈cycloalkyl. In oneembodiment, R⁷ is H. In another embodiment, R⁷ is taken together with R⁶to form —C₃₋₈cycloalkyl, for example cyclopentyl.

One particular embodiment of the invention provides for an activecompound of formula I where Ar**—COOH represents Ar—R¹ and R⁵ is—C₀₋₃alkylene-SH. One corresponding prodrug (prodrug A) can contain athioester linkage, which can be cleaved in vivo to form the —COOH(R¹)and —C₀₋₃alkylene-SH(R⁵) moieties. Another corresponding prodrug(prodrug B, where Z is —C₁₋₆alkylene, optionally substituted with one ormore moieties such as hydroxyl, phenyl, carboxyl, and so forth),contains both an ester and a thioester group, which can be similarlycleaved in vivo, but which also releases a physiologically acceptableacid such as α-hydroxy acid (Z is —CH₂—), β-hydroxy acid (Z is—(CH₂)₂—), (R)-2-hydroxypropionic or lactic acid (Z is —CH(CH₃)—),(R)-hydroxyphenyl acetic or mandelic acid (Z is —CH(phenyl)-), salicylicacid (Z is -phenylene-), 2,3-dihydroxysuccinic or tartaric acid (Z is—CH[CH(OH)(COOH)]—), citric acid (Z is —C[CH₂COOH]₂—), hydroxy bis- andhydroxy-tris acids, and so forth.

Yet another corresponding prodrug (prodrug C) is a dimer form of prodrugA, thus containing two thioester linkages, which can both be cleaved invivo to form two active moieties, each containing the —COOH(R¹) and—C₀₋₃alkylene-SH(R⁵) moieties.

Examples of prodrug A and C are described in Example 33.

Another embodiment of the invention provides for an active compound offormula I where R⁵ is —C₀₋₃alkylene-SH, and the prodrug (prodrug D) is adimer form of the compound:

One example of prodrug D is the dimer form of the compound of Example19(c). MS m/z: [M+H⁺] calcd for C₅₆H₆₆F₂N₆O₈S₂, 1053.44. found 1053.6.

In one embodiment of the invention, the compound of formula I is thespecies embodied in formula IIa:

where Ar, R²⁻³, X, and R⁵⁻⁷ are as defined for formula I; andpharmaceutically acceptable salts thereof. In one particular embodiment,Ar is selected from:

R¹ is selected from —COOR^(1a), —NHSO₂R^(1b), —SO₂NHR^(1d), —SO₂OH,—O—CH(R^(1e))—COOH, and tetrazol-5-yl; where R^(a) is H, —C₁ ₋₆alkyl,—C₁₋₃alkylenearyl, —C₁₋₃alkyleneheteroaryl, —C₃₋₇cycloalkyl, —CH(C₁₋₄alkyl)OC(O)R^(1aa), or

R^(1aa) is —O—C₁₋₆alkyl or —O—C₃₋₇cycloalkyl; R^(1b) is R^(1c); R^(1c)is —C₁₋₆alkyl or —C₀₋₄alkylenearyl; R^(1d) is H, —C(O)R^(1c), or—C(O)NHR^(ic); R^(1e) is —C₁₋₄alkyl; R² is selected from H, halo,—C₁₋₆alkyl, —C₃₋₆cycloalkyl, and —C₀₋₅alkylene-OR^(2b); where R^(2b) isselected from H and —C₀₋₆alkyl; R³ is selected from —C₁₋₁₀alkyl and—C₀₋₅allylene-O—C₀₋₅alkylene-C₁₋₆alkyl; X is —C₁₋₁₁alkylene-, where 1 to4 —CH₂— moieties in the alkylene are replaced with a —NR^(4a)—C(O)— or—C(O)—NR^(4a)— moiety, where R^(4a) is selected from H and —OH; R⁵ isselected from —C₀₋₃alkylene-SR^(5a), —C₀₋₃alkylene-C(O)NR^(5b)R^(5c),—NH—C₀₋₁alkylene-P(O)(OR^(5e))₂, —C₀₋₂alkylene-CHR^(5g)—COOH and—C₀₋₃alkylene-C(O)NR^(5h)—CHR^(5i)—COOH; R^(5a) is H or —C(O)—R^(5aa);R^(5aa) is —C₁₋₆ alkyl, —C₀₋₆alkylene-C₃₋₇cycloalkyl, —C₀₋₆alkylenearyl,or —C₀₋₆alkylenemorpholine; R^(5b) is H, —OH, —OC(O)R^(5ba), —CH₂COOH,or —OC(S)NR^(5bb)R^(5bc); R^(5ba) is —OCH₂-aryl or —CH₂O-aryl; R^(5bb)and R^(5bc) are independently —C₁₋₄alkyl; R⁵ is H; R^(5e) is H; R^(5g)is —CH₂—O—(CH₂)₂—O—CH₃; R^(5h) is H; and R^(5i) is —C₀₋₃alkylenearyl; R⁶is selected from —C₁₋₆alkyl, —C₀₋₃alkylenearyl, —C₀₋₃alkyleneheteroaryl,and —C₀₋₃alkylene-C₃₋₇cycloalkyl; and R⁷ is H or is taken together withR⁶ to form -cyclopentyl. In one embodiment, each ring in Ar and eacharyl in R¹⁻³ and R⁵⁻⁶, each carbon atom in X, and each alkyl and eacharyl in R¹⁻³, R^(4a-4d), and R⁵⁻⁶ are optionally substituted as definedfor formula I. In yet another embodiment, each ring in Ar and each arylin R¹ and R⁵⁻⁶ is optionally substituted with 1 to 2 substituentsindependently selected from —C₁₋₆alkyl, —CN, halo, —O—C₁₋₆alkyl, and—NO₂, wherein each alkyl is optionally substituted with 1 to 5 fluoroatoms; each carbon atom in X is optionally substituted with one R^(4b)group and one —CH₂-moiety in X may be replaced with a group selectedfrom —C₄₋₈cycloalkylene-, —CR^(4d)═CH—, and —CH═CR^(4d)—; wherein R^(4b)is —C₀₋₅alkylene-COOR^(4c) or benzyl; R^(4c) is H; and R^(4d) is—CH₂-thiophene; and each alkyl and each aryl in R¹ and R⁶ is optionallysubstituted with 1 to 7 fluoro atoms. In yet another embodiment, onering in Ar is substituted with 1 or 2 fluoro atoms.

In one particular embodiment of compounds of formula IIa, R¹ is selectedfrom —COOH, —OC(O)(C₁₋₆alkyl), —NHSO₂(C₁₋₆alkyl), and—SO₂NH[—C(O)(C₁₋₆alkyl)]; R² is selected from H, halo, —C₁₋₆alkyl,—C₃₋₆cycloalkyl and —C₀₋₅alkylene-OH; R³ is—C₀₋₅alkylene-O—C₀₋₅alkylene-C₁₋₆allyl; X is —C₁₋₁₁alkylene-, where 1 to4 —CH₂— moieties in the alkylene are replaced with —NHC(O)— or —C(O)NH—;R⁵ is —C₀₋₃alkylene-SR^(5a) or —C₀₋₃alkylene-C(O)NH(OH); R^(5a) is H or—C(O)—R^(5aa); R^(5aa) is —C₁₋₆alkyl, —C₀₋₆alkylenearyl, or—C₀₋₆alkylenemorpholine; R⁶ is selected from —C₁₋₆alkyl,—C₀₋₃alkylenearyl, and —C₀₋₃alkylene-C₃₋₇cycloalkyl; and R⁷ is H. In oneembodiment, each ring in Ar and each aryl in R¹ and R⁶ is optionallysubstituted with 1 to 2 halo groups; and each alkyl and each aryl in R¹and R⁶ is optionally substituted with 1 to 7 fluoro atoms. In yetanother embodiment, one ring in Ar is substituted with 1 or 2 fluoroatoms. In one particular embodiment, X is —C₁₋₅alkylene-, and in anotherembodiment, X is selected from —C(O)NH— and —CH₂—NHC(O)—.

In one embodiment of the invention, the compound of formula I is thespecies embodied in formula IIIa:

where Ar, R³, X, and R⁵⁻⁷ are as defined for formula I; andpharmaceutically acceptable salts thereof. In one particular embodiment,Ar is selected from:

R¹ is —COOR^(1a), where R^(1a) is H or —C₁₋₆alkyl; R³ is —C₁₋₁₀alkyl; Xis —CH₂—NHC(O)—; R⁵ is selected from —C₀₋₃alkylene-SR^(5a) and—C₀₋₃alkylene-C(O)N(OH)H; R^(5a) is H or —C(O)C₁₋₆alkyl; R⁶ is selectedfrom —C₁₋₆alkyl and —C₀₋₃alkylenearyl; and R⁷ is H. In one embodiment,each ring in Ar and the aryl in R⁶, the carbon atom in X, and each alkyland each aryl in R¹, R³, and R⁵⁻⁶ are optionally substituted as definedfor formula I.

In one embodiment of the invention, the compound of formula I is thespecies embodied in formula IVa:

where Ar, R²⁻³, X, and R⁵⁻⁷ are as defined for formula I; andpharmaceutically acceptable salts thereof. In one particular embodiment,Ar is:

R¹ is —COOR^(1a), where R^(1a) is H or —C₁₋₆alkyl; R² is H; R³ is—C₁₋₁₀alkyl; X is —CH₂—NHC(O)—; R⁵ is selected from—C₀₋₃alkylene-SR^(5a) and —C₀₋₃alkylene-C(O)N(OH)H; R^(5a) is H or—C(O)C₁₋₆alkyl; R⁶ is selected from —C₁₋₆alkyl and —C₀₋₃alkylenearyl;and R⁷ is H. In one embodiment, each ring in Ar and the aryl in R⁶, thecarbon atom in X, and each alkyl and each aryl in R¹, R³, and R⁵⁻⁶ areoptionally substituted as defined for formula I.

In one embodiment of the invention, the compound of formula I is thespecies embodied in formula Va:

where Ar, R²⁻³, X, and R⁵⁻⁷ are as defined for formula I; andpharmaceutically acceptable salts thereof. In one particular embodiment,Ar is:

R¹ is —COOR^(1a), where R^(1a) is H or —C₁₋₆alkyl; R² is H; R³ is—C₁₋₁₀alkyl; X is —C(O)NH—; R⁵ is selected from —C₀₋₃alkylene-SR^(5a)and —C₀₋₃alkylene-C(O)N(OH)H; R^(5a) is H or —C(O)C₁₋₆alkyl; R⁶ is—C₀₋₃alkylenearyl; and R⁷ is H. In one embodiment, the ring in Ar andthe aryl in R⁶, and each alkyl and each aryl in R¹, R³, and R⁵⁻⁶ areoptionally substituted as defined for formula I.

In one embodiment of the invention, the compound of formula I is thespecies embodied in formula VIa:

where Ar, R³, X, and R⁵⁻⁷ are as defined for formula I; andpharmaceutically acceptable salts thereof. In one particular embodiment,Ar is selected from:

R¹ is —COOR^(1a), where R^(1a) is H or —C₁₋₆alkyl; R³ is —C₁₋₁₀alkyl; Xis —C(O)NH— or —CH₂—NHC(O)—; R⁵ is selected from —C₀₋₃alkylene-SR^(5a)and —C₀₋₃alkylene-C(O)N(OH)H; R^(5a) is H or —C(O)C₁₋₆alkyl; R⁶ isselected from —C₁₋₆alkyl and —C₀₋₃alkylenearyl; and R⁷ is H. In oneembodiment, each ring in Ar and the aryl in R⁶, the carbon atom in X,and each alkyl and each aryl in R¹, R³, and R⁵⁻⁶ are optionallysubstituted as defined for formula I.

In one embodiment of the invention, the compound of formula I is thespecies embodied in formula VII:

where Y is —C(R³)—, Z is —N—, Q is —C(R²)— and W is a bond; Y is —N—, Zis —C(R³)—, Q is —C(R²)— and W is a bond; Y is —C(R³)—, Z is —N—, Q is—N— and W is a bond; or Y is —C(R³)—, Z is —CH—, Q is —C(R²)— and W is—C(O)—; and R²⁻³, Ar, X, and R⁵⁻⁷ are as defined for formula I; andpharmaceutically acceptable salts thereof.

In another particular embodiment, Ar is selected from:

R¹ is selected from —COOR^(1a), —NHSO₂R^(1b), —SO₂NHR^(1d), —SO₂OH,—O—CH(R^(1e))—COOH, and tetrazol-5-yl; where R^(1a) is H, —C₁₋₆alkyl,—C₁₋₃alkylenearyl, —C₁₋₃alkyleneheteroaryl, —C₃₋₇cycloalkyl,—CH(C₁₋₄alkyl)OC(O)R^(1aa), or

R^(1aa) is —O—C₁₋₆alkyl or —O—C₃₋₇cycloalkyl; R^(1b) is R^(1c); R^(1c)is —C₁₋₆alkyl or —C₀₋₄alkylenearyl; R^(1d) is H, —C(O)R^(1c), or—C(O)NHR^(1c); R^(1e) is —C₁₋₄alkyl; R² is selected from H, halo,—C₁₋₆alkyl, —C₃₋₆cycloalkyl, and —C₀₋₅alkylene-OR^(2b); where R^(2b) isselected from H and —C₁₋₆alkyl; R³ is selected from —C₁₋₁₀alkyl and—C₀₋₅alkylene-O—C₀₋₅alkylene-R^(3b); where R^(3b) is —C₁₋₆alkyl; X is—C₁₋₁₁alkylene-, where 1 to 4 —CH₂— moieties in the alkylene arereplaced with a —NR^(4a)—C(O)— or —C(O)—NR^(4a)— moiety, where R^(4a) isselected from H and —OH; R⁵ is selected from —C₀₋₃alkylene-SR^(5a),—C₀₋₃alkylene-C(O)NR^(5b)R^(5c), —NH—C₀₋₁alkylene-P(O)(OR^(5e))₂,—C₀₋₂alkylene-CHR^(5g)—COOH and —C₀₋₃alkylene-C(O)NR^(5h)—CHR^(5i)—COOH;R^(5a) is H or —C(O)—R^(5aa); R^(5aa) is —C₁₋₆alkyl,—C₀₋₆alkylene-C₃₋₇cycloalkyl, —C₀₋₆alkylenearyl, or—C₀₋₆alkylenemorpholine; R^(5b) is H, —OH, —OC(O)R^(5ba), —CH₂COOH, or—OC(S)NR^(5bb)R^(5bc); R^(5ba) is —OCH₂-aryl or —CH₂O-aryl; R^(5bb) andR^(5bc) are independently —C₁₋₄alkyl; R⁵ is H; R^(5e) is H; R^(5g) is—CH₂—O—(CH₂)₂—O—CH₃; R^(5b) is H; and R^(5i) is —C₀₋₃alkylenearyl; R⁶ isselected from —C₁₋₆alkyl, —C₀₋₃alkylenearyl, —C₀₋₃alkyleneheteroaryl,and —C₀₋₃alkylene-C₃₋₇cycloalkyl; and R⁷ is H or is taken together withR⁶ to form —C₃₋₈cycloalkyl. In one embodiment, each ring in Ar and eacharyl in R³⁻⁶ and R⁵⁻⁶, each carbon atom in X, and each alkyl and eacharyl in R¹⁻³, R^(4a-4d), and R⁵⁻⁶ are optionally substituted as definedfor formula I. In yet another embodiment, each ring in Ar and each arylin R¹ and R⁵⁻⁶ is optionally substituted with 1 to 2 substituentsindependently selected from —C₁₋₆alkyl, —CN, halo, —O—C₁₋₆alkyl, and—NO₂, wherein each alkyl is optionally substituted with 1 to 5 fluoroatoms; each carbon atom in X is optionally substituted with one R^(4b)group and one —CH₂-moiety in X may be replaced with a group selectedfrom —C₄₋₈cycloalkylene-, —CR^(4d)═CH—, and —CH═CR^(4d)—; wherein R^(4b)is —C₀₋₅alkylene-COOR^(4c) or benzyl; R^(4c) is H; and R^(4d) is—CH₂-thiophene; and each alkyl and each aryl in R¹ and R⁶ is optionallysubstituted with 1 to 7 fluoro atoms. In another aspect, theseembodiments have formula II, IIa, III, IIIa, IV, IVa, V, Va, VI, VIa orVII.

In another particular embodiment, X is selected from the group:—C(O)NH—; —CH₂—NHC(O)—; —C(O)NH—CH₂—; —C(O)NH—NHC(O)—;—CH═C(—CH₂-2-thiophene)-C(O)NH—; —(CH₂)₂—NHC(O)—;—C(O)NH—CH₂—CH(COOH)—CH₂—; —C(O)NH—CH(benzyl)-CH₂—NHC(O)—;—C(O)NH—CH(benzyl)-CH₂—C(O)NH—; —CH₂—NHC(O)—CH₂—NHC(O)—;—CH₂—NHC(O)-cyclohexylene-NHC(O)—; —CH₂—N(OH)C(O)-cyclohexylene-NHC(O)—;—CH₂—NHC(O)—CH₂—CH(COOH)—NHC(O)—; —CH₂—NHC(O)—(CH₂)₂—NHC(O)—;—C(O)NH—(CH₂)₂—C(O)N(OH)—CH₂—; —C(O)NH—(CH₂)₂—CH(COOH)—NHC(O)—;—C(O)NH—(CH₂)₄—NHC(O)—; —CH₂—NHC(O)—(CH₂)₂—CH(COOH)—NHC(O)—;—C(O)NH—(CH₂)₃—CH(COOH)—NHC(O)—; —C(O)NH—(CH₂)₂—NHC(O)—CH₂—NHC(O)—;—C(O)NH—(CH₂)₂—NHC(O)-cyclohexylene-NHC(O)—; —CH₂—NHC(O)—(CH₂)₄—NHC(O)—;—C(O)NH—(CH₂)₄—CH(COOH)—NHC(O)—;—CH₂—NHC(O)—(CH₂)₂—NHC(O)-cyclohexylene-NHC(O)—;—CH₂—C(O)NH—(CH₂)₂—NHC(O)-cyclohexylene-NHC(O)—;—C(O)NH—(CH₂)₄—NHC(O)—CH₂—NHC(O)—;—C(O)NH—(CH₂)₄—NHC(O)-cyclohexylene-NHC(O)—; —CH₂—NHC(O)—(CH₂)₆—NHC(O)—;—CH₂—NHC(O)—(CH₂)₄—NHC(O)-cyclohexylene-NHC(O)—;—C(O)NH—(CH₂)₆—NHC(O)-cyclohexylene-NHC(O)—; and—CH₂—NHC(O)—(CH₂)₆—NHC(O)-cyclohexylene-NHC(O)—. In another aspect, thisembodiment has formula II, IIa, III, IIIa, IV, IVa, V, Va, VI, VIa orVII.

In one particular embodiment, Ar is selected from:

In another aspect, this embodiment has formula II, IIa, III, IIIa, IV,IVa, V, Va, VI, VIa or VII.

In another particular embodiment, R¹ is selected from —COOH,—NHSO₂R^(1b), —SO₂NHR^(1d), —SO₂OH, —C(O)NH—SO₂R^(1c), —P(O)(OH)₂, —CN,—O—CH(R^(1e))—COOH, tetrazol-5-yl,

where R^(1b), R^(1c), R^(1d), and R^(1e), are as defined for formula I.In one particular embodiment, R¹ is selected from —COOR^(1a),—SO₂NHR^(1d), and tetrazol-5-yl. In another embodiment, R¹ is selectedfrom —COOH, —SO₂NHC(O)—C₁₋₆allyl, and tetrazol-5-yl. In another aspect,these embodiments have formula II, IIa, III, IIIa, IV, IVa, V, Va, VI,VIa or VII.

In one particular embodiment, R¹ is —COOR^(1a), where R^(1a) is—C₁₋₆alkyl, —C₁₋₃alkylenearyl, —C₁₋₃alkyleneheteroaryl, —C₃₋₇cycloalkyl,—CH(C₁₋₄alkyl)OC(O)R^(1aa), —C₀₋₆alkylenemorpholine,

where R^(1aa) is as defined for formula I. In one aspect of theinvention, these compounds may find particular utility as prodrugs or asintermediates in the synthetic procedures described herein. In oneparticular embodiment, R¹ is —COOR^(1a) and R^(1a) is —C₁₋₆alkyl. Inanother aspect, these embodiments have formula II, IIa, III, IIIa, IV,IVa, V, Va, VI, VIa or VII.

In one particular embodiment, R¹ is selected from —COOR^(1a) andtetrazol-5-yl, where R^(1a) is H or —C₁₋₆alkyl. In another aspect, thisembodiment has formula II, IIa, III, IIIa, IV, IVa, V, Va, VI, VIa orVII.

In one embodiment, R⁵ is selected from —C₀₋₃alkylene-SR^(5a),—C₀₋₃alkylene-C(O)NR^(5b)R^(5c), and —C₀₋₃alkylene-NR^(5b)—C(O)R^(5d),—NH—C₀₋₁alkylene-P(O)(OR^(5e))₂, —C₀₋₃alkylene-P(O)OR^(5e)R^(5f),—C₀₋₂alkylene-CHR^(5g)—COOH, and —C₀₋₃alkylene-C(O)NR^(5h),—CHR^(5i)—COOH; where R^(5a) is H, R^(5b) is —OH, R^(5c) is H, R^(5d) isH, R^(5e) is H; and R^(5f), R^(5g), R^(5h), R^(5i) are as defined forformula I. More particularly, in one embodiment, R⁵ is selected from—C₀₋₁alkylene-SH, —C₀₋₁alkylene-C(O)—N(OH)H, and—C₀₋₃alkylene-N(OH)—C(O)H. In another embodiment, R⁵ is selected from—C₀₋₃alkylene-SR^(5a) and —C₀₋₃alkylene-C(O)NR^(5h)R^(5c), where R^(5a)is H; R^(5b) is —OH. In one particular embodiment, R⁵ is H. In anotheraspect, these embodiments have formula II, IIa, III, IIIa, IV, IVa, V,Va, VI, VIa or VII.

In yet another embodiment, R⁵ is selected from —C₀₋₃alkylene-SR^(5a),—C₀₋₃alkylene-C(O)NR^(5b)R^(5c), —C₀₋₃alkylene-NR^(5b)—C(O)R^(5d),—NH—C₀₋₁alkylene-P(O)(OR^(5e))₂, —C₀₋₃alkylene-P(O)OR^(5e)R^(5f), and—C₀₋₃alkylene-S—SR^(5j); where R^(5a) is —C(O)—R^(5aa); R^(5b) is H,—OC(O)R^(5ba), —CH₂COOH, —O-benzyl, -pyridyl, or —OC(S)NR^(5bb)R^(5bc);R^(5e) is —C₁₋₆alkyl, —C₁₋₃alkylenearyl, —C₁₋₃alkyleneheteroaryl,—C₃₋₇cycloalkyl, —CH(CH₃)—O—C(O)R^(5ea),

and where R^(5aa), R^(5ba), R^(5bb), R^(5bc), R^(5c), R^(5d), R^(5ea),R^(5f), and R^(5j) are defined for formula I. In one aspect of theinvention, these compounds may find particular utility as prodrugs or asintermediates in the synthetic procedures described herein. In anotheraspect, these embodiments have formula II, IIa, III, IIIa, IV, IVa, V,Va, VI, VIa or VII.

In one particular embodiment, R⁵ is selected from —C₀₋₃alkylene-SR^(5a)and —C₀₋₃alkylene-C(O)NR^(5b)R^(5c); where R^(5a) is selected from H and—C(O)—C₁₋₆alkyl; R^(5b) is selected from H, —OH, and —OC(O)—C₁₋₆alkyl;and R^(5c) is selected from H and —C₁₋₆alkyl. In another aspect, thisembodiment has formula II, IIa, III, Ma, IV, IVa, V, Va, VI, VIa or VII.

In another embodiment, R¹ is selected from —COOR^(1a) where R^(1a) is H,—NHSO₂R^(1b), —SO₂NHR^(1d), —SO₂OH, —C(O)NH—SO₂R^(1c), —P(O)(OH)₂, —CN,—O—CH(R^(1e))—COOH, tetrazol-5-yl,

R⁵ is selected from —C₀₋₃alkylene-SR^(5a),—C₀₋₃alkylene-C(O)NR^(5b)R^(5c), and —C₀₋₃alkylene-NR^(5b)—C(O)R^(5d),—NH—C₀₋₁alkylene-P(O)(OR^(5e))₂, —C₀₋₃alkylene-P(O)OR^(5e)R^(5f),—C₀₋₂alkylene-CHR^(5g)—COOH, and—C₀₋₃alkylene-C(O)NR^(5h)—CHR^(5i)—COOH; R^(5a) is H, R^(5b) is —OH,R^(5c) is H, R^(5d) is H, R^(5e) is H; and R^(5f), R^(5g), R^(5h),R^(5i) are as defined for formula I. In one particular embodiment, R¹ isselected from —COOH, —SO₂NHR^(1d), and tetrazol-5-yl; and R⁵ is selectedfrom —C₀₋₃alkylene-SH, and —C₀₋₃alkylene-C(O)N(OH)H. In another aspect,these embodiments have formula II, IIa, III, IIIa, IV, IVa, V, Va, VI,VIa or VII.

In another embodiment, R¹ is —COOR^(1a), where R^(1a) is —C₁₋₆alkyl,—C₁₋₃alkylenearyl, —C₁₋₃alkyleneheteroaryl, —C₃₋₇cycloalkyl,—CH(C₁₋₄alkyl)OC(O)R^(1aa), —C₀₋₆alkylenemorpholine,

R⁵ is selected from —C₀₋₃allylene-SR^(5a),—C₀₋₃alkylene-C(O)NR^(5b)R^(5c), —C₀₋₃alkylene-NR^(5b)—C(O)R^(5d),—NH—C₀₋₁alkylene-P(O)(OR^(5e))₂, —C₀₋₃allylene-P(O)OR^(5e)R^(5f), and—C₀₋₃alkylene-S—SR^(5j); where R^(5a) is —C(O)—R^(5aa); R^(5b) is H,—OC(O)R^(5ba), —CH₂COOH, —O-benzyl, -pyridyl, or —OC(S)NR^(5bb)R^(5bc);R^(5e) is —C₁₋₆alkyl, —C₁₋₃alkylenearyl, —C₁₋₃alkyleneheteroaryl,—C₃₋₇cycloalkyl, —CH(CH₃)—O—C(O)R^(5ea),

and where R^(5aa), R^(5ba), R^(5bb), R^(5bc), R^(5c), R^(5d), R^(5ea),R^(5f), and R^(5j) are as defined for formula I. In another aspect, thisembodiment has formula II, IIa, III, IIIa, IV, IVa, V, Va, VI, VIa orVII.

A particular group of compounds of formula I are those disclosed in U.S.Provisional Application No. 60/925,931, filed on Apr. 24, 2007. Thisgroup includes compounds of formula (I′):

wherein: Y′ is —C(R³′)—, Z′ is —N—, Q′ is —C(R²′)— and A′ is a bond; Y′is —N—, Z′ is —C(R³′)—, Q′ is —C(R^(2′))— and A′ is a bond; Y′ is—C(R³′)—, Z′ is —N—, Q′ is —N— and A′ is a bond; Y′ is —C(R³′)—, Z′ is—CH—, Q′ is —N— and A′ is a bond; or Y′ is —C(R³′)—, Z′ is —CH—, Q′ is—C(R²′)— and A′ is —C(O)—; r′ is 0, 1 or 2; Ar′ is an aryl groupselected from:

R¹′ is selected from —COOR^(1a)′, —NHSO₂—C₁₋₆alkyl, —NHSO₂aryl,—NHSO₂NHC(O)—C₁₋₆alkyl, —NHSO₂NHC(O)-aryl, —SO₂NHC(O)—C₁₋₆alkyl,—SO₂NHC(O)-aryl, —SO₂NHC(O)NH—C₁₋₆alkyl, —SO₂NHC(O)NH-aryl, —SO₂OH,—SO₂NH₂, —SO₂NH—C₁₋₆alkyl, —SO₂NH-aryl, —C(O)NH—SO₂—C₁₋₆alkyl,—C(O)NH—SO₂-aryl, —P(O)(OH)₂, —CN, —OCH(CH₃)—COOH, —OCH(aryl)-COOH,tetrazol-5-yl,

where R^(1a)′ is selected from H, —C₁₋₆alkyl, benzyl,—C₁₋₃alkyleneheteroaryl, cycloalkyl, —CH(CH₃)OC(O)R^(1b)′,

R^(1b)′ is selected from —O—C₁₋₆alkyl, —O-cycloalkyl, —NR^(1c)′R^(1d)′,—CH(NH₂)CH₂COOCH₃; and R^(1c)′ and R^(1d)′ are independently selectedfrom H, —C₁₋₆alkyl, and benzyl, or are taken together as —(CH₂)₃₋₆—; R²′is selected from H, —CH₂OH, halo, —NO₂, —C₁₋₆alkyl, —C₂₋₆alkenyl,—C₃₋₆cycloalkyl, —CN, —C(O)R^(2a), and —C₀₋₃alkylenearyl; where R^(2a)′is selected from H, —C₁₋₆alkyl, —C₃₋₆cycloalkyl, —C₀₋₃alkylene-phenyl,—OR^(2b)′ and —NR^(2c)′R^(2d)′; R^(2b)′ is selected from H, —C₁₋₆alkyl,—C₃₋₆cycloalkyl, phenyl and benzyl; and R^(2c)′ and R^(2d)′ areindependently selected from H, —C₁₋₄alkyl, and —C₀₋₁alkylene-phenyl; R³′is selected from —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₃₋₁₀alkynyl,—C₃₋₇cycloalkyl, —C₀₋₃alkylene-C₃₋₇cycloalkyl,—C₀₋₃alkenylene-C₃₋₇cycloalkyl, —C₀₋₃alkynylene-C₃₋₇cycloalkyl,—(CH₂)₀₋₅NR^(3a)′(CH₂)₀₋₅R^(3b)′, —(CH₂)₀₋₅O(CH₂)₁₋₅R^(3b)′,—(CH₂)₁₋₅S(CH₂)₁₋₅R^(3b)′, and —C₀₋₃alkylenearyl; where R^(3a)′ isselected from H, —C₃₋₆cycloalkyl, and —C₀₋₁alkylene-phenyl; and R^(3b)′is selected from H, —C₁₋₆alkyl, —C₃₋₆cycloalkyl, —C₂₋₄alkenyl,—C₂₋₄alkynyl, and phenyl; R⁴′ is —X′—CR⁵′R⁶′R⁷′; X′ is C₁₋₁₂alkylene,where at least one —CH₂— moiety in the alkylene is replaced with a—NR^(4a)′—C(O)— or —C(O)—NR^(4a)′-moiety, where R^(4a)′ is selected fromH, —OH, and —C₁₋₄alkyl; R⁵′ is selected from —C₀₋₃alkylene-SR^(5a)′,—C₀₋₃alkylene-C(O)NR^(5b)′R^(5c)′, —C₀₋₃alkylene-NR^(5b)′—C(O)R^(5d)′,—C₀₋₁alkylene-NHC(O)CH₂SH, —NH—C₀₋₁alkylene-P(O)(OH)₂,—C₀₋₃allylene-P(O)OH—R^(5e)′, —C₀₋₂alkylene-CHR^(5f)′-COOH and—C₀₋₃alkylene-C(O)NR^(5g)′-CHR^(5b)′—COOH; where R^(5a)′ is selectedfrom H, —C(O)—C₁₋₆alkyl, —C(O)—C₀₋₆alkylene-C₃₋₇cycloalkyl,—C(O)—C₀₋₆alkylenearyl, and —C(O)—C₀₋₆alkyleneheteroaryl; R^(5b)′ isselected from H, —OH, —OC(O)C₁₋₆alkyl, —CH₂COOH, —O-benzyl, -pyridyl,—OC(O)OCH₂-phenyl, —OC(O)CH₂O-phenyl, —OC(O)N(CH₃)₂, and —OC(S)N(CH₃)₂;R^(5c)′ is selected from H, —C₁₋₆alkyl, and —C(O)—R^(5c)″, where R^(5c)″is selected from —C₁₋₆alkyl, —C₃₋₇cycloalkyl, aryl, and heteroaryl;R^(5d)′ is selected from H, —C₀₋₃alkylenearyl, —NR⁵d″R^(5d)′″, and—O—C₁₋₆alkyl, where R^(5d)″ and R^(5d)′″ are independently selected fromH and —C₁₋₄alkyl; R^(5e)′ is selected from H, —C₀₋₃alkylenearyl,—C₁₋₃alkylene-NR^(5e)″R^(5e)′″, and—C₁₋₃alkylene(aryl)-C₀₋₃alkylene-NR^(5e)″R^(5e)′″, where R^(5e)′ andR^(5e)′″ are independently selected from H and —C₁₋₄alkyl; R^(5f)′ isselected from H, —C₁₋₆alkyl, —C₁₋₃alkylenearyl, and —CH₂—O—(CH₂)₂—OCH₃;R^(5g)′ is selected from H and —C₁₋₄alkyl; and R^(5h)′ is selected fromH, C₁₋₄alkyl, and —C₀₋₃alkylenearyl; R⁶′ is selected from —C₁₋₆alkyl,—CH₂—O—(CH₂)₂OCH₃, —C₁₋₆alkylene-O—C₁₋₆alkyl, —C₀₋₃alkylenearyl,—C₀₋₃alkyleneheteroaryl, and —C₀₋₃alkylene-C₃₋₇cycloalkyl; and R⁷′ is Hor is taken together with R⁶′ to form —C₃₋₈cycloalkyl; wherein: each—CH₂— group in —(CH₂)_(r′)— is optionally substituted with 1 or 2substituents independently selected from —C₁₋₄alkyl and fluoro; eachalkyl and each aryl in R¹′⁻⁴′ is optionally substituted with 1 to 7fluoro atoms; each ring in Ar′ and each aryl in R¹′⁻⁴′ is optionallysubstituted with 1 to 3 substituents independently selected from —OH,—C₁₋₆alkyl, —C₂₋₄alkenyl, —C₂₋₄alkynyl, —CN, halo, —O(C₁₋₆alkyl),—S(C₁₋₆alkyl), —S(O)(C₁₋₆alkyl), —S(O)₂(C₁₋₄alkyl), -phenyl, —NO₂, —NH₂,—NH(C₁₋₆alkyl) and —N(C₁₋₆alkyl)₂, wherein each alkyl, alkenyl andalkynyl is optionally substituted with 1 to 5 fluoro atoms; and eachcarbon atom in the alkylene moiety in X′ is optionally substituted withone more R^(4b)′ groups and one —CH₂— moiety in X′ may be replaced with—C₄₋₈cycloalkylene; wherein R^(4b′) is selected from —C₀₋₅alkylene-COOH,—C₁₋₆alkyl, —C₀₋₁alkylene-CONH₂, —C₁₋₂alkylene-OH,—C₀₋₃alkylene-C₃₋₇cycloalkyl, and benzyl; and pharmaceuticallyacceptable salts thereof.

In one particular embodiment of the compound of formula (I′), Y′represents —C(R³′)—, Z′ is —N—, Q′ is —C(R²′)— and A′ is a bond, whichcan be represented as:

In addition, particular compounds of formula I that are of interestinclude those set forth in the Examples below, as well as thepharmaceutically acceptable salts thereof.

DEFINITIONS

When describing the compounds, compositions, methods and processes ofthe invention, the following terms have the following meanings unlessotherwise indicated. Additionally, as used herein, the singular forms“a,” “an,” and “the” include the corresponding plural forms unless thecontext of use clearly dictates otherwise. The terms “comprising”,“including,” and “having” are intended to be inclusive and mean thatthere may be additional elements other than the listed elements.

The term “pharmaceutically acceptable” refers to a material that is notbiologically or otherwise undesirable. For example, the term“pharmaceutically acceptable carrier” refers to a material that can beincorporated into a composition and administered to a patient withoutcausing undesirable biological effects or interacting in a deleteriousmanner with other components of the composition. Such pharmaceuticallyacceptable materials typically have met the required standards oftoxicological and manufacturing testing, and include those materialsidentified as suitable inactive ingredients by the U.S. Food and Drugadministration.

The term “pharmaceutically acceptable salt” means a salt prepared from abase or an acid which is acceptable for administration to a patient,such as a mammal (for example, salts having acceptable mammalian safetyfor a given dosage regime). However, it is understood that the saltscovered by the invention are not required to be pharmaceuticallyacceptable salts, such as salts of intermediate compounds that are notintended for administration to a patient. Pharmaceutically acceptablesalts can be derived from pharmaceutically acceptable inorganic ororganic bases and from pharmaceutically acceptable inorganic or organicacids. In addition, when a compound of formula I contains both a basicmoiety, such as an amine, pyridine or imidazole, and an acidic moietysuch as a carboxylic acid or tetrazole, zwitterions may be formed andare included within the term “salt” as used herein. Salts derived frompharmaceutically acceptable inorganic bases include ammonium, calcium,copper, ferric, ferrous, lithium, magnesium, manganic, manganous,potassium, sodium, and zinc salts, and the like. Salts derived frompharmaceutically acceptable organic bases include salts of primary,secondary and tertiary amines, including substituted amines, cyclicamines, naturally-occurring amines and the like, such as arginine,betaine, caffeine, choline, N,N′-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperadine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine and the like. Salts derived frompharmaceutically acceptable inorganic acids include salts of boric,carbonic, hydrohalic (hydrobromic, hydrochloric, hydrofluoric orhydroiodic), nitric, phosphoric, sulfamic and sulfuric acids. Saltsderived from pharmaceutically acceptable organic acids include salts ofaliphatic hydroxyl acids (for example, citric, gluconic, glycolic,lactic, lactobionic, malic, and tartaric acids), aliphaticmonocarboxylic acids (for example, acetic, butyric, formic, propionicand trifluoroacetic acids), amino acids (for example, aspartic andglutamic acids), aromatic carboxylic acids (for example, benzoic,p-chlorobenzoic, diphenylacetic, gentisic, hippuric, and triphenylaceticacids), aromatic hydroxyl acids (for example, o-hydroxybenzoic,p-hydroxybenzoic, 1-hydroxynaphthalene-2-carboxylic and3-hydroxynaphthalene-2-carboxylic acids), ascorbic, dicarboxylic acids(for example, fumaric, maleic, oxalic and succinic acids), glucoronic,mandelic, mucic, nicotinic, orotic, pamoic, pantothenic, sulfonic acids(for example, benzenesulfonic, camphosulfonic, edisylic, ethanesulfonic,isethionic, methanesulfonic, naphthalenesulfonic,naphthalene-1,5-disulfonic, naphthalene-2,6-disulfonic andp-toluenesulfonic acids), xinafoic acid, and the like.

As used herein, the term “prodrug” is intended to mean an inactive (orsignificantly less active) precursor of a drug that is converted intoits active form in the body under physiological conditions, for example,by normal metabolic processes. The term is also intended to includecertain protected derivatives of compounds of formula I that may be madeprior to a final deprotection stage. Such compounds may not possesspharmacological activity at AT₁ and/or NEP, but may be administeredorally or parenterally and thereafter metabolized in the body to formcompounds of the invention which are pharmacologically active at AT₁and/or NEP. Thus, all protected derivatives and prodrugs of compoundsformula I are included within the scope of the invention. Prodrugs ofcompounds of formula I having a free carboxyl, sulfhydryl or hydroxygroup can be readily synthesized by techniques that are well known inthe art. These prodrug derivatives are then converted by solvolysis orunder physiological conditions to be the free carboxyl, sulfhydryland/or hydroxy compounds. Exemplary prodrugs include: esters includingC₁₋₆alkylesters and aryl-C₁₋₆alkylesters, carbonate esters, hemi-esters,phosphate esters, nitro esters, sulfate esters, sulfoxides, amides,carbamates, azo-compounds, phosphamides, glycosides, ethers, acetals,ketals, and disulfides. In one embodiment, the compounds of formula Ihave a free sulfhydryl or a free carboxyl and the prodrug is an esterderivative.

The term “solvate” means a complex or aggregate formed by one or moremolecules of a solute, for example, a compound of formula I or apharmaceutically acceptable salt thereof, and one or more molecules of asolvent. Such solvates are typically crystalline solids having asubstantially fixed molar ratio of solute and solvent. Representativesolvents include, by way of example, water, methanol, ethanol,isopropanol, acetic acid and the like. When the solvent is water, thesolvate formed is a hydrate.

The term “therapeutically effective amount” means an amount sufficientto effect treatment when administered to a patient in need thereof, thatis, the amount of drug needed to obtain the desired therapeutic effect.For example, a therapeutically effective amount for treatinghypertension could be the amount of drug needed to reduce blood pressureor the amount of drug needed to maintain normal blood pressure. On theother hand, the term “effective amount” means an amount sufficient toobtain a desired result, which may not necessary be a therapeuticresult. For example, when studying a system comprising an AT₁ receptor,an “effective amount” may be the amount needed to antagonize thereceptor.

The term “treating” or “treatment” as used herein means the treating ortreatment of a disease or medical condition (such as hypertension) in apatient, such as a mammal (particularly a human) that includes: (a)preventing the disease or medical condition from occurring, that is,prophylactic treatment of a patient; (b) ameliorating the disease ormedical condition such as by eliminating or causing regression of thedisease or medical condition in a patient; (c) suppressing the diseaseor medical condition such as by slowing or arresting the development ofthe disease or medical condition in a patient; or (d) alleviating thesymptoms of the disease or medical condition in a patient. For example,the term “treating hypertension” would include preventing hypertensionfrom occurring, ameliorating hypertension, suppressing hypertension, andalleviating the symptoms of hypertension (for example, lowering bloodpressure). The term “patient” is intended to include those mammals, suchas humans, that are in need of treatment or disease prevention or thatare presently being treated for disease prevention or treatment of aspecific disease or medical condition. The term “patient” also includestest subjects in which compounds of the invention are being evaluated ortest subjects being used in a assay, for example an animal model.

The term “alkyl” means a monovalent saturated hydrocarbon group whichmay be linear or branched. Unless otherwise defined, such alkyl groupstypically contain from 1 to 10 carbon atoms and include, for example,—C₁₋₄alkyl, —C₁₋₆allyl, and —C₁₋₁₀alkyl. Representative alkyl groupsinclude, by way of example, methyl, ethyl, n-propyl, isopropyl, n-butyl,s-butyl, isobutyl, t-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl,n-nonyl, n-decyl and the like.

When a specific number of carbon atoms is intended for a particular termused herein, the number of carbon atoms is shown preceding the term assubscript. For example, the term “—C₁₋₆alkyl” means an alkyl grouphaving from 1 to 6 carbon atoms, and the term “—C₃₋₆cycloalkyl” means acycloalkyl group having from 3 to 6 carbon atoms, where the carbon atomsare in any acceptable configuration.

The term “alkylene” means a divalent saturated hydrocarbon group thatmay be linear or branched. Unless otherwise defined, such alkylenegroups typically contain from 0 to 10 carbon atoms and include, forexample, —C₀₋₁alkylene-, —C₀₋₂alkylene-, —C₀₋₃ alkylene-, —C₀₋₅alkylene-, —C₀₋₆alkylene-, —C₁₋₂alkylene- and —C₁₋₁₂alkylene-.Representative alkylene groups include, by way of example, methylene,ethane-1,2-diyl (“ethylene”), propane-1,2-diyl, propane-1,3-diyl,butane-1,4-diyl, pentane-1,5-diyl and the like. It is understood thatwhen the alkylene term include zero carbons such as —C₀₋₁alkylene- or—C₀₋₅alkylene-, such terms are intended to include a single bond.

The term “alkylthio” means a monovalent group of the formula —S-alkyl,where alkyl is as defined herein. Unless otherwise defined, suchalkylthio groups typically contain from 1 to 10 carbon atoms andinclude, for example, —S—C₁₋₄alkyl and —S—C₁₋₆alkyl. Representativealkylthio groups include, by way of example, ethylthio, propylthio,isopropylthio, butylthio, s-butylthio and t-butylthio.

The term “alkenyl” means a monovalent unsaturated hydrocarbon groupwhich may be linear or branched and which has at least one, andtypically 1, 2 or 3, carbon-carbon double bonds. Unless otherwisedefined, such alkenyl groups typically contain from 2 to 10 carbon atomsand include, for example, —C₂₋₄alkenyl and —C₂₋₁₀alkenyl. Representativealkenyl groups include, by way of example, ethenyl, n-propenyl,isopropenyl, n-but-2-enyl, n-hex-3-enyl and the like. The term“alkenylene” means a divalent alkenyl group, and includes groups such as—C₂₋₃alkenylene-.

The term “alkoxy” means a monovalent group of the formula —O-alkyl,where alkyl is as defined herein. Unless otherwise defined, such alkoxygroups typically contain from 1 to 10 carbon atoms and include, forexample, —O—C₁₋₄allyl and —O—C₁₋₆alkyl. Representative alkoxy groupsinclude, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy,n-butoxy, sec-butoxy, isobutoxy, t-butoxy and the like.

The term “alkynyl” means a monovalent unsaturated hydrocarbon groupwhich may be linear or branched and which has at least one, andtypically 1, 2 or 3, carbon-carbon triple bonds. Unless otherwisedefined, such alkynyl groups typically contain from 2 to 10 carbon atomsand include, for example, —C₂₋₄alkynyl and —C₃₋₁₀alkynyl. Representativealkynyl groups include, by way of example, ethynyl, n-propynyl,n-but-2-ynyl, n-hex-3-ynyl and the like. The term “alkynylene” means adivalent alkynyl group and includes groups such as —C₂₋₃alkynylene.

Amino acid residues are often designated as —C(O)—CHR—NH—, where the Rmoiety is referred to as the “amino acid side chain.” Thus, for theamino acid valine, HO—C(O)—CH[—CH(CH₃)₂]—NH₂, the side chain is—CH(CH₃)₂. Ther term “amino acid side chain” is intended to include sidechains of the twenty common naturally occurring amino acids: alanine,arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine,glycine, histidine, isoleucine, leucine, lysine, methionine,phenylalanine, proline, serine, threonine, tryptophan, tyrosine, andvaline. Of particular interest are the side chains of non-polar aminoacids such as isoleucine, leucine, and valine.

The term “aryl” means a monovalent aromatic hydrocarbon having a singlering (for example, phenyl) or fused rings. Fused ring systems includethose that are fully unsaturated (for example, naphthalene) as well asthose that are partially unsaturated (for example,1,2,3,4-tetrahydronaphthalene). Unless otherwise defined, such arylgroups typically contain from 6 to 10 carbon ring atoms and include, forexample, —C₆₋₁₀aryl. Representative aryl groups include, by way ofexample, phenyl and naphthalene-1-yl, naphthalene-2-yl, and the like.The term “arylene” means a divalent aryl group such as phenylene.

The term “cycloalkyl” means a monovalent saturated carbocyclichydrocarbon group. Unless otherwise defined, such cycloalkyl groupstypically contain from 3 to 10 carbon atoms and include, for example,—C₃₋₅cycloalkyl, —C₃₋₆cycloalkyl and —C₃₋₇cycloalkyl. Representativecycloalkyl groups include, by way of example, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and the like. The term “cycloalkylene” means adivalent aryl group such as —C₄₋₈cycloalkylene.

The term “halo” means fluoro, chloro, bromo and iodo.

The term “heteroaryl” means a monovalent aromatic group having a singlering or two fused rings and containing in the ring(s) at least oneheteroatom (typically 1 to 3) selected from nitrogen, oxygen or sulfur.Unless otherwise defined, such heteroaryl groups typically contain from5 to 10 total ring atoms and include, for example, —C₂₋₉heteroaryl.Representative heteroaryl groups include, by way of example, monovalentspecies of pyrrole, imidazole, thiazole, oxazole, furan, thiophene,triazole, pyrazole, isoxazole, isothiazole, pyridine, pyrazine,pyridazine, pyrimidine, triazine, indole, benzofuran, benzothiophene,benzoimidazole, benzthiazole, quinoline, isoquinoline, quinazoline,quinoxaline and the like, where the point of attachment is at anyavailable carbon or nitrogen ring atom.

The term “optionally substituted” means that group in question may beunsubstituted or it may be substituted one or several times, such as 1to 3 times or 1 to 5 times. For example, an alkyl group that is“optionally substituted” with 1 to 5 fluoro atoms, may be unsubstituted,or it may contain 1, 2, 3, 4, or 5 fluoro atoms.

The term “protected derivatives thereof” means a derivative of thespecified compound in which one or more functional groups of thecompound are protected or blocked from undergoing undesired reactionswith a protecting or blocking group. Functional groups that may beprotected include, by way of example, carboxy groups, amino groups,hydroxyl groups, thiol groups, carbonyl groups and the like.Representative protecting groups for carboxy groups include esters (suchas a p-methoxybenzyl ester), amides and hydrazides; for amino groups,carbamates (such as t-butoxycarbonyl) and amides; for hydroxyl groups,ethers and esters; for thiol groups, thioethers and thioesters; forcarbonyl groups, acetals and ketals; and the like. Such protectinggroups are well-known to those skilled in the art and are described, forexample, in T. W. Greene and G. M. Wuts, Protecting Groups in OrganicSynthesis, Third Edition, Wiley, New York, 1999, and references citedtherein.

All other terms used herein are intended to have their ordinary meaningas understood by those of ordinary skill in the art to which theypertain.

General Synthetic Procedures

Compounds of the invention can be prepared from readily availablestarting materials using the following general methods, the proceduresset forth in the Examples, or by using other methods, reagents, andstarting materials that are known to those of ordinary skill in the art.Although the following procedures may illustrate a particular embodimentof the invention, it is understood that other embodiments of theinvention can be similarly prepared using the same or similar methods orby using other methods, reagents and starting materials known to thoseof ordinary skill in the art. It will also be appreciated that wheretypical or preferred process conditions (for example, reactiontemperatures, times, mole ratios of reactants, solvents, pressures,etc.) are given, other process conditions can also be used unlessotherwise stated. While optimum reaction conditions will typically varydepending on various reaction parameters such as the particularreactants, solvents and quantities used, those of ordinary skill in theart can readily determine suitable reaction conditions using routineoptimization procedures.

Additionally, as will be apparent to those skilled in the art,conventional protecting groups may be necessary or desired to preventcertain functional groups from undergoing undesired reactions. Thechoice of a suitable protecting group for a particular functional groupas well as suitable conditions and reagents for protection anddeprotection of such functional groups are well-known in the art.Protecting groups other than those illustrated in the proceduresdescribed herein may be used, if desired. For example, numerousprotecting groups, and their introduction and removal, are described inT. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis,Third Edition, Wiley, New York, 1999, and references cited therein. Morespecifically, the following abbreviations and reagents are used in theschemes presented below:

P¹ represents an “amino-protecting group,” a term used herein to mean aprotecting group suitable for preventing undesired reactions at an aminogroup. Representative amino-protecting groups include, but are notlimited to, t-butoxycarbonyl (BOC), trityl (Tr), benzyloxycarbonyl(Cbz), 9-fluorenylmethoxycarbonyl (Fmoc), formyl, trimethylsilyl (TMS),t-butyldimethylsilyl (TBDMS), and the like. Standard deprotectiontechniques are used to remove the P¹ group. For example, deprotection ofan N—BOC group can involve reagents such as TFA in DCM or HCl in1,4-dioxane, while a Cbz group can be removed by employing catalytichydrogenation conditions such as H₂ (1 atm), 10% Pd/C in an alcoholicsolvent.

P² represents a “carboxy-protecting group,” a term used herein to mean aprotecting group suitable for preventing undesired reactions at acarboxy group. Representative carboxy-protecting groups include, but arenot limited to, methyl, ethyl, t-butyl, benzyl (Bn), p-methoxybenzyl(PMB), 9-fluorenylmethyl (Fm), trimethylsilyl (TMS),t-butyldimethylsilyl (TBDMS), diphenylmethyl (benzhydryl, DPM) and thelike. Standard deprotection techniques and reagents are used to removethe P² group, and may vary depending upon which group is used. Forexample, NaOH is commonly used when P² is methyl, an acid such as TFA orHCl is commonly used when P² is t-butyl, and catalytic hydrogenationcondition such as H₂ (1 atm) and 10% Pd/C in alcoholic solvent(“H₂/Pd/C”) may be used when P² is benzyl.

P³ represents a “thiol-protecting group,” a term used herein to mean aprotecting group suitable for preventing undesired reactions at a thiolgroup. Representative thiol-protecting groups include, but are notlimited to, ethers, esters such as —C(O)CH₃, and the like. Standarddeprotection techniques and reagents such as NaOH, primary alkylamines,and hydrazine, may be used to remove the P³ group.

P⁴ represents a “tetrazole-protecting group,” a term used herein to meana protecting group suitable for preventing undesired reactions at atetrazole group. Representative tetrazole-protecting groups include, butare not limited to trityl and diphenylmethyl. Standard deprotectiontechniques and reagents such as TFA in DCM or HCl in 1,4-dioxane may beused to remove the P⁴ group.

P⁵ represents a “hydroxyl-protecting group,” a term that is used hereinto mean a protecting group suitable for preventing undesired reactionsat a hydroxyl group. Representative hydroxyl-protecting groups include,but are not limited to C₁₋₆alkyls, silyl groups includingtriC₁₋₆alkylsilyl groups, such as trimethylsilyl (TMS), triethylsilyl(TES), and tert-butyldimethylsilyl (TBDMS); esters (acyl groups)including C₁₋₆alkanoyl groups, such as formyl, acetyl, and pivaloyl, andaromatic acyl groups such as benzoyl; arylmethyl groups such as benzyl(Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm), and diphenylmethyl(benzhydryl, DPM); and the like. Standard deprotection techniques andreagents are used to remove the P⁵ group, and may vary depending uponwhich group is used. For example, H₂/Pd/C is commonly used when P⁵ isbenzyl, while NaOH is commonly used when P⁵ is an acyl group.

P⁶ represents a “sulfonamide-protecting group,” a term that is usedherein to mean a protecting group suitable for preventing undesiredreactions at a sulfonamide group. Representative sulfonamide-protectinggroups include, but are not limited to t-butyl and acyl groups.Exemplary acyl groups include aliphatic lower acyl groups such as theformyl, acetyl, phenylacetyl, butyryl, isobutyryl, valeryl, isovaleryland pivaloyl groups, and aromatic acyl groups such as the benzoyl and4-acetoxybenzoyl. Standard deprotection techniques and reagents are usedto remove the P⁶ group, and may vary depending upon which group is used.For example, HCl is commonly used when P⁶ is t-butyl, while NaOH iscommonly used when P⁶ is an acyl group.

P⁷ represents a “phosphate-protecting group or phosphinate-protectinggroup,” a term used herein to mean a protecting group suitable forpreventing undesired reactions at a phosphate or phosphinate group.Representative phosphate and phosphinate protecting groups include, butare not limited to C₁₋₄alkyls, aryl (for example, phenyl) andsubstituted aryls (for example, chlorophenyl and methylphenyl). Theprotected group can be represented by —P(O)(OR)₂, where R is a groupsuch as a C₁₋₆alkyl or phenyl. Standard deprotection techniques andreagents such as TMS-I/2,6-lutidine, and H₂/Pd/C are used to remove theP⁷ group such as ethyl, and benzyl, respectively.

In addition, L is used to designate a “leaving group,” a term usedherein to mean a functional group or atom which can be displaced byanother functional group or atom in a substitution reaction, such as anucleophilic substitution reaction. By way of example, representativeleaving groups include chloro, bromo and iodo groups; sulfonic estergroups, such as mesylate, triflate, tosylate, brosylate, nosylate andthe like; and acyloxy groups, such as acetoxy, trifluoroacetoxy and thelike.

Suitable bases for use in these schemes include, by way of illustrationand not limitation, potassium carbonate, calcium carbonate, sodiumcarbonate, triethylamine, pyridine, 1,8-diazabicyclo-[5.4.0]undec-7-ene(DBU), N,N-diisopropylethylamine (DIPEA), sodium hydroxide, potassiumhydroxide, potassium t-butoxide, and metal hydrides.

Suitable inert diluents or solvents for use in these schemes include, byway of illustration and not limitation, tetrahydrofuran (THF),acetonitrile (MeCN), N,N-dimethylformamide (DMF), dimethyl sulfoxide(DMSO), toluene, dichloromethane (DCM), chloroform (CHCl₃), carbontetrachloride (CCl₄), 1,4-dioxane, methanol, ethanol, water, and thelike.

Suitable carboxylic acid/amine coupling reagents includebenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(BOP), benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate(PyBOP), O-(7-azabenzotriazol-1-yl-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU), dicyclohexylcarbodiimide (DCC),N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDC),carbonyldiimidazole (CDI), and the like. Coupling reactions areconducted in an inert diluent in the presence of a base, and areperformed under conventional amide bond-forming conditions.

All reactions are typically conducted at a temperature within the rangeof about −78° C. to 100° C., for example at room temperature. Reactionsmay be monitored by use of thin layer chromatography (TLC), highperformance liquid chromatography (HPLC), and/or LCMS until completion.Reactions may be complete in minutes, or may take hours, typically from1-2 hours and up to 48 hours. Upon completion, the resulting mixture orreaction product may be further treated in order to obtain the desiredproduct. For example, the resulting mixture or reaction product may besubjected to one or more of the following procedures: concentrating orpartitioning (for example, between EtOAc and water or between 5% THF inEtOAc and 1M phosphoric acid); extraction (for example, with EtOAc,CHCl₃, DCM, HCl); washing (for example, with saturated aqueous NaCl,saturated NaHCO₃, Na₂CO₃ (5%), CHCl₃ or 1M NaOH); drying (for example,over MgSO₄, over Na₂SO₄, or in vacuo); filtering; crystallizing (forexample, from EtOAc and hexane); and/or being concentrated (for example,in vacuo).

By way of illustration, compounds of formula I, as well as their salts,solvates, and prodrugs can be prepared by one or more of the followingexemplary processes.

Scheme I: Peptide Coupling Reaction and Optional Deprotection

The X moiety contains one or more amide groups, and therefore thecompounds of the invention may be formed by a coupling reaction underconventional amide bond-forming conditions, followed by a deprotectionstep if needed. In Scheme I, the A and B moieties couple to form X, andthe sum of a and b is in the range of 0 to 11. Thus, one moietycomprises an amine group and one moiety comprises a carboxylic acidgroup, i.e., A is —NH₂ and B is —COOH or A is —COOH and B is —NH₂.

For example, to synthesize a compound of formula I where X is —CONH—, Awould be —COOH and B would be —NH₂. Similarly, A as —NH₂ and B as —COOHwould couple to form —NHCO— as the X moiety. A and B can be readilymodified if a longer X is desired, whether it contains an alkyleneportion or additional amide groups. For example, A as —CH₂NH₂ and B as—COOH would couple to form —CH₂NHCO— as the X moiety.

It is understood that the carbon atoms in the —(CH₂)_(a) and —(CH₂)_(b)groups make up the “X” linker. Therefore, these carbon atoms may besubstituted with one or more R^(4b) groups. Furthermore, one —CH₂— groupin the —(CH₂)_(a) or the —(CH₂)_(b) group may be replaced with a—C₄₋₈cycloalkylene-, —CR^(4d)═CH—, or —CH═CR^(4d)— group.

Ar* represents Ar—R¹*, where R¹* may represent R¹ as defined herein, ora protected form of R¹ (for example, -tetrazol-5-yl-P⁴ or —C(O)O—P² suchas —C(O)O—C₁₋₆alkyl), or a precursor of R¹ (for example, —CN that isthen converted to tetrazole, or nitro that is then converted to aminofrom which the desired R¹ is prepared). R⁵* represents R⁵ as definedherein, or a protected form of R⁵. Therefore, when R¹* represents R¹ andR⁵* represents R⁵, the reaction is complete after the coupling step.

On the other hand, when R¹* represents a protected form of R¹ and/or R⁵*represents a protected form of R⁵, a subsequent global or sequentialdeprotection step would yield the non-protected compound. Similarly,when R¹* represents a precursor of R¹, a subsequent conversion stepwould yield the desired compound. Reagents and conditions for thedeprotection vary with the nature of protecting groups in the compound.Typical deprotection conditions when R⁵* represents C₀₋₃alkylene-S—P³,include treating the compound with NaOH in an alcoholic solvent at 0° C.or room temperature to yield the non-protected compound. Typicaldeprotection conditions when R¹* represents C(O)O—P² where P² refers tot-butyl include treating the compound with TFA in DCM at roomtemperature to yield the non-protected compound. Thus, one method ofpreparing compounds of the invention involves coupling compounds (1) and(2), with an optional deprotection step when R¹* is a protected form ofR¹ and/or R⁵* is a protected form of R⁵, thus forming a compound offormula I or a pharmaceutically acceptable salt thereof.

Examples of compound (1) include:4′-(5-aminomethyl-2-butyl-4-chloroimidazol-1-ylmethyl)biphenyl-2-carboxylicacid t-butyl ester;2-butyl-3-(4-methoxycarbonylbenzyl)-3H-imidazole-4-carboxylic acid;4-(5-aminomethyl-2-butyl-imidazol-1-ylmethyl)-2,3-difluorobenzoic acidmethyl ester;C-{2-butyl-3-[2′-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-3H-imidazol-4-yl}methylamine;4′-(3-aminomethyl-5-propyl[1,2,4]triazol-4-ylmethyl)biphenyl-2-carboxylicacid;4′-(3-aminomethyl-6-butyl-2-oxo-2H-pyridin-1-ylmethyl)biphenyl-2-carboxylicacid;4′-(5-aminomethyl-2-ethoxy-4-ethylimidazol-1-ylmethyl)biphenyl-2-carboxylicacid t-butyl ester;4′-(5-aminomethyl-2-ethoxy-4-ethylimidazol-1-ylmethyl)-3′-fluorobiphenyl-2-carboxylicacid t-butyl ester;4′-(5-aminomethyl-2-propoxy-4-ethylimidazol-1-ylmethyl)-3′-fluorobiphenyl-2-carboxylicacid t-butyl ester; and4′-(5-aminomethyl-4-chloro-2-ethoxyimidazol-1-ylmethyl)-3′-fluorobiphenyl-2-carboxylicacid t-butyl ester.

Examples of compound (2) include:(R)-1-benzyl-2-hydroxycarbamoylethyl)-carbamic acid;(R)-2-((R)-2-amino-3-phenylpropyldisulfanyl)-1-benzylethylamine;(S)-2-acetylsulfanyl-4-methylpentanoic acid;2-acetylsulfanylmethyl-4-methyl-pentanoic acid and(S)-2-acetylsulfanylmethyl-4-methylpentanoic acid; and(R)-2-(2-benzyloxycarbamoyl-3-phenypropionylamino)succinic acid 1-methylester.

Compound (1)

Compound (1) can be prepared by the following reaction:

Compounds (1a) and (1b) are combined with K₂CO₃ in a solvent such as DMFto form intermediate (1c), which then undergoes oxime formation byreaction with hydroxylamine hydrochloride (NH₂OH.HCl) in pyridine toform intermediate (1d). Intermediate (1d) is reacted with NaBH₃CN,NH₄OAc, and TiCl₃, in a solvent such as MeOH, to form Compound (1) whereA is —NH(R^(4a)). Compound (1) where A is —COOH can be formed byreacting intermediate (1c) with 2-methyl-2-butene, sodium dihydrogenphosphate and sodium chlorite.

Compound (1a)

Compound (1a) can be readily prepared by techniques that are well knownin the art and/or is commercially available. Examples of compound (1a)include 2-butyl-5-chloro-3H-imidazole-4-carbaldehyde,5-bromo-2-butyl-3H-imidazole-4-carbaldehyde,5-bromo-2-ethoxy-3H-imidazole-4-carbaldehyde,bromo-2-propoxy-3H-imidazole-4-carbaldehyde, and5-chloro-2-ethoxy-3H-imidazole-4-carbaldehyde, all of which are eithercommercially available or are readily synthesized by techniques that arewell known in the art. For example:5-bromo-2-butyl-3H-imidazole-4-carbaldehyde can be made reacting2-butyl-3H-imidazole-4-carbaldehyde with N-bromosuccinimide in asuitable solvent such as DMF;5-bromo-2-ethoxy-3H-imidazole-4-carbaldehyde can be prepared by reacting2,4,5-tribromo-1H-imidazole with [β-(trimethylsilyl)ethoxy]methylchloride, followed by reaction with potassium t-butoxide in ethanol,then n-butyllithium and DMF, with a final deprotection step; and5-chloro-2-ethoxy-3H-imidazole-4-carbaldehyde can be prepared byreacting4,5-dibromo-2-ethoxy-1-(2-trimethylsilanylethoxymethyl)-1H-imidazole andhexachloroethane then DMF, both steps conducted with n-butyllithium,N,N,N′,N′-tetramethylethylenediamine, and appropriate solvents, with afinal deprotection step.

Compound (1b)

The starting material (1e) can be prepared using synthetic methods thatare reported in the literature, for example Duncia et al. (1991) J. Org.Chem. 56: 2395-400, and references cited therein. Alternatively, thestarting material in a protected form (10 may be commercially available.Using a commercially available non-protected starting material (1e), theR¹ group is first protected to form protected intermediate (10, then theleaving group (L) is added to form compound (1b), for example, by ahalogenation reaction. For example, a bromination reaction of a methylgroup of N-triphenylmethyl-5-[4′-methylbiphenyl-2-yl]tetrazole isdescribed in Chao et al. (2005) J. Chinese Chem. Soc. 52:539-544. Inaddition, when Ar* has a —CN group, it can be subsequently converted tothe desired tetrazolyl group, which may be protected. Conversion of thenitrile group is readily achieved by reaction with a suitable azide suchas sodium azide, trialkyltin azide (particularly tributyltin azide) ortriaryltin azide. Compound (1b) when Ar has one of the remainingformulas is readily synthesized using similar techniques or othermethods as are well known in the art.

Exemplary methods of preparing compound (1b) include the following. Asolution of the starting material (1e) and thionyl chloride are stirredat room temperature. After completion, the reaction is concentrated invacuo to afford a solid, which is dissolved in a solvent such as THF andcooled to 0° C. Potassium t-butoxide is then added. Upon completion, thereaction is partitioned between EtOAc and water. The organic layer iswashed with saturated aqueous NaCl, dried over MgSO₄, filtered, andconcentrated to afford compound (10. Alternately, HCl is added to asolution of the starting material (1e) and a solvent such as methanol.The reaction is heated to reflux and stirred until completion (˜48hours), then cooled and concentrated. The recovered material is dried invacuo to obtain intermediate (1f). Intermediate (1f), benzoyl peroxide,and N-bromosuccinimide are dissolved in CCl₄ or benzene, and heated toreflux. The reaction is stirred to completion, cooled to roomtemperature, filtered, and concentrated in vacuo. The resulting residueis crystallized from diethyl ether and hexane or flash chromatographedto give compound (1b). Examples of compound (1e) include:4′-methylbiphenyl-2-carboxylic acid; 2,3-difluoro-4-methyl-benzoic acid;and 2-fluoro-4-methylbenzoic acid. Examples of compound (1f) includeN-triphenylmethyl-5-[4′-methylbiphenyl-2-yl]tetrazole.

Compound (1b) where R¹ is —SO₂NHR^(1d) may be synthesized as follows:

The starting material, 2-bromobenzene-1-sulfonamide, is commerciallyavailable.

Reaction of 2-bromobenzene-1-sulfonamide in a solvent such as DMF, with1,1-dimethoxy-N,N-dimethylmethanamine, followed by the addition ofsodium hydrogen sulfate in water, yields2-bromo-N-[1-dimethylaminometh-(E)-ylidene]benzenesulfonamide. Thiscompound is reacted with 4-methylphenylboronic acid to yield4′-methylbiphenyl-2-sulfonic acid 1-dimethylaminometh-(E)-ylideneamide,then the —(CH₂)_(r)-L¹ moiety is added, for example, by a halogenationreaction, to form compound (1b).

Compound (1b) where the Ar moiety is substituted may be synthesized asfollows:

The starting material, 2-bromobenzoic acid, is commercially available.Reaction of 2-bromobenzoic acid in a suitable solvent, with t-butylalcohol, DCC and DMAP, yields 2-bromo-benzoic acid t-butyl ester. Thiscompound is reacted with 3-fluoro-4-methylphenylboronic acid to yield3′-fluoro-4′-methyl-biphenyl-2-carboxylic acid t-butyl ester, then the—(CH₂)_(r)-L¹ moiety is added, for example, by a halogenation reaction,to form compound (1b).

Examples of compound (1b) include5-(4′-bromomethylbiphenyl-2-yl)-1-trityl-1H-tetrazole;4′-bromomethylbiphenyl-2-carboxylic acid t-butyl ester;4-bromomethylbenzoic acid methyl ester;4-bromomethyl-2,3-difluorobenzoic acid methyl ester;4′-formyl-biphenyl-2-sulfonic acid t-butylamide;4′-aminomethylbiphenyl-2-carboxylic acid t-butyl ester; and4′-bromomethyl-3′-fluorobiphenyl-2-carboxylic acid t-butyl ester.

Compound (2)

Compound (2) is readily synthesized by following the techniquesdescribed in the literature, for example, Neustadt et al (1994) J. Med.Chem. 37:2461-2476 and Moree et al. (1995) J. Org. Chem. 60: 5157-69, aswell as by using the exemplary procedures described below. Examples ofCompound (2), depicted without chirality, include:

Since compound (2) has a chiral center, it may be desirable tosynthesize a particular stereoisomer, and examples are provided asfollows.

Preparation of Chiral Amino Hydroxamate Compound (2^(i))

A base such as DIPEA and a coupling agent such as EDC are added to asolution of compound (2a) in DMF containing HOBt and hydroxylaminehydrochloride. The mixture is stirred at room temperature untilcompletion (˜12 hours), then concentrated in vacuo. The resultingmaterial is distributed between 5% THF in EtOAc and 1M phosphoric acid.The organic layer is collected and washed with a base such as 1M NaOH.The alkaline aqueous layer is then acidified, for example with 1Mphosphoric acid, and extracted with EtOAc. The organic layer isevaporated and the residue purified by silica gel chromatography toafford compound (2^(i)). Examples of compound (2a) include(R)-3-t-butoxycarbonylamino-4-phenylbutyric acid.

Preparation of Chiral Amino Sulfhydryl Dimer Compound (2^(ii))

Diisopropyl azodicarboxylate is added to a solution oftriphenylphosphine in a solvent such as THF, cooled in an ice bath. Thesolution is stirred and compound (2b) and thioacetic acid are added. Themixture is stirred at 0° C. for 1 hour, then stirred at room temperatureuntil completion (˜12 hours). The mixture is stripped, diluted withEtOAc, and washed with a cold saturated NaHCO₃ solution. The organiclayer is dried over MgSO₄, and the filtrate evaporated to dryness. Theresulting material is flash chromatographed to provide compound (2c).Compound (2c) is dissolved in solvent, followed by the addition of abase such as 1M LiOH. Air is bubbled through the solution for 1 hourfollowed by the addition of solvent. The reaction is stirred at roomtemperature until completion (˜24 hours). The solution is then acidifiedto pH˜5, for example with acetic acid. The precipitate is filtered andrinsed with deionized water, producing the compound (2d) dimer. Thesolid is suspended in MeCN, then concentrated under reduced pressure.The recovered material is dissolved in 4M HCl in 1,4-dioxane and stirredat room temperature until the reaction is complete (˜2 hours). Thereaction is then concentrated under reduced pressure, and trituratedwith EtOAc. The product is filtered, washed with EtOAc, and dried invacuo to provide compound (2^(ii)). Examples of compound (2b) include((R)-1-benzyl-2-hydroxyethyl)carbamic acid t-butyl ester.

Preparation of Chiral Sulfanyl Acid Compound (2^(iii))

Compound (2e) is formed by dissolving a compound such as D-leucine (forR⁶=isobutyl, for example) in 3M HBr (aqueous) and cooled to 0° C. Asolution of NaNO₂ in water is added, and the reaction stirred at 0° C.until completion (˜2.5 hours). The reaction is then extracted withEtOAc, washed with saturated aqueous NaCl, dried over MgSO₄, filtered,and concentrated to afford compound (2e). Compound (2e) is combined withpotassium thioacetate or sodium thioacetate and DMF, and the reactionstirred at room temperature until completion (˜1 hour). Water is added.The reaction is then extracted with EtOAc, washed with saturated aqueousNaCl, dried over MgSO₄, filtered, and concentrated to provide compound(2^(iii)). The product is purified by silica gel chromatography.Examples of compound (2e) include (R)-2-bromo-4-methylpentanoic acid.Examples of compound (2^(iii)) include(S)-2-acetylsulfanyl-4-methylpentanoic acid.

Preparation of Sulfanyl Acid Compound (2^(iv))

Compound (20 is mixed with diethylamine and cooled in an ice bath. Anaqueous formaldehyde solution (37%) is then added, and the mixturestirred at 0° C. for approximately 2 hours, warmed to room temperatureand stirred overnight. The mixture is then extracted with ether, washed,dried, and evaporated to dryness, to provide compound (2g). Compound(2g) is then dissolved in 1,4-dioxane, and a 1M NaOH solution is added.The mixture is stirred at room temperature until completion(approximately 2 days). The organic solvent is removed in vacuo, and theaqueous residue is rinsed with EtOAc and acidified to approximately pH 1with concentrated HCl. The product is extracted with EtOAc, dried, andevaporated to dryness to yield compound (2h). Compound (2h) is combinedwith thiolacetic acid (10 mL), and the mixture is stirred at 80° C.until completion (approximately 2 hours), then concentrated to drynessto yield compound (2^(iv)), which is dissolved in toluene andconcentrated to remove any trace of thiolacetic acid. Examples ofcompound (2f) include 2-benzylmalonic acid monoethyl ester (R⁶=benzyl)and 2-isobutylmalonic acid monoethyl ester (R⁶=isobutyl).

Preparation of Chiral Sulfanyl Acid Compound (2^(v))

Compound (21), (S)-4-benzyl-2-oxazolidinone, is commercially available.Compound (2j) is also typically commercially available or can be readilysynthesized. For example, R⁶—CH₂—COOH (for example, isocaproic acid or3-phenylpropionic acid) is dissolved in methylene chloride and thionylchloride is added. The mixture is stirred at room temperature until thereaction is complete (for example, overnight), and then concentrated toprovide (2j). Examples of compound (2j) include 4-methylpentanoylchloride and 3-phenylpropionyl chloride.

Compound (2i) is dissolved in a suitable solvent and cooled (−78° C.)under nitrogen. n-Butyllithium in hexanes is added dropwise and stirred,followed by the addition of (2j) dropwise. The mixture is stirred at−78° C., then warmed to 0° C. Saturated NaHCO₃ is added and the mixturewarmed to room temperature. The mixture is extracted, washed, dried,filtered, and concentrated to afford (2k). Compound (2k) is dissolved inDCM and stirred at 0° C. under nitrogen. 1M Titanium tetrachloride isadded, followed by 1,3,5-trioxane, all in appropriate solvents. A secondequivalent of 1M titanium tetrachloride is added and the mixture stirredat 0° C. until the reaction is complete. The reaction is then quenchedwith saturated ammonium chloride. Appropriate solvents are added, theaqueous phase is extracted, and the organic layers are combined, dried,filtered, and concentrated to provide (2l), which can then be purifiedby silica gel chromatography or used in the next step without furtherpurification. Compound (2l) is dissolved in a solvent, to which is added9 M hydrogen peroxide in water, followed by the dropwise addition of 1.5M lithium hydroxide monohydrate in water. The mixture is warmed to roomtemperature and stirred. Optionally, potassium hydroxide may be addedand the mixture heated at 60° C. then cooled at room temperature. Tothis is added an aqueous solution of sodium sulfite followed by waterand chloroform. The aqueous layer is extracted, acidified and extractedagain. The organic layer is washed, dried, filtered, and rotovaped toprovide (2m). Triphenylphosphine is dissolved in an appropriate solventand cooled at 0° C. (ice bath). Diisopropyl azodicarboxylate is addeddropwise and the mixture stirred. Compound (2m) and thioacetic acid,dissolved in an appropriate solvent, are added dropwise to the mixture.After the addition, the mixture is removed from the ice bath and stirredat room temperature until the reaction is complete (approximately 3.5hours), concentrated, and then partitioned. The organic layer isextracted and the combined aqueous extracts washed, acidified andextracted. The organic layer is washed again, dried, filtered, androtovaped to provide compound (2^(v)). Examples of compound (2^(v))include (S)-2-acetylsulfanylmethyl-4-methylpentanoic acid.

Scheme II: Peptide Coupling Reaction

Compounds of formula I can also be prepared by coupling compound (3) andcompound (1) where A is —COOH, followed by reaction with compound (4).In compounds (1) and (3), the sum of a and b is in the range of 0 to 11.In compounds (3) and (4), the [R⁵] and moieties represent portions ofthe R⁵ moiety. For example, if R⁵ is —CH₂C(O)N(OH)H, then [R⁵] would be—CH₂C(O)— and would be —N(OH)H.

The amide coupling of compounds (1) and (3) is typically conducted atroom temperature with coupling reagents such as pentafluorophenolcombined with EDC and DIPEA in solvents such as DMF. Compounds (3) and(4) are available commercially or can be readily synthesized bytechniques that are well known in the art. Examples of compound (3)include 3-amino-4-(3-chlorophenyl)butyric acid. Examples of compound (4)include H₂NOH, H₂NO-benzyl, and H₂NO-t-butyl.

Scheme III: Peptide Coupling Reaction

Compounds of formula I can also be prepared by coupling compounds (1)and (5) under conventional amide bond-forming conditions. This synthesisis particularly useful for preparing compounds of formula I where morethan one —CH₂— moiety in the alkylene is replaced with —NR^(4a)—C(O)— or—C(O)—NR^(4a)—. In the compounds depicted below, b will typically be atleast 1 and the sum of a, b and c is in the range of 1 to 10.

Compound (5) is formed by converting the ester compound (6) to the acidwith a base, converting the acid to the dioxopyrrolidinyl ester withN-hydroxysuccinimide, then converting the dioxopyrrolidinyl ester withcompound (7) to form compound (5). Compound (5) may have one or moreR^(4b) substituents on the carbon atoms in the —(CH₂)_(b)— and/or—(CH₂)_(c)— portions.

Compound (6) can be readily synthesized by following the techniquesdescribed in the literature, for example, Fournie-Zaluski et al. (1985)J. Med. Chem. 28(9):1158-1169). Examples of compound (6) include2-benzyl-N-benzyloxymalonamic acid ethyl ester. Compound (7) isavailable commercially or can be readily synthesized by techniques thatare well known in the art. This reactant is particularly useful where acarbon atom in the alkylene moiety in X is substituted with an R^(4b)group. For example, 2-aminosuccinic acid 1-methyl ester is an example ofcompound (7) that is useful for preparing compounds where R^(4b) is—COOH, where the R^(4b) moiety is in a protected form, —COOMe.

Scheme IV: Two-Step Reaction

Compounds of formula I can also be prepared by a two-step method, wherethe first step involves the addition of a halogen-substituted alkanoicacid (“L-acid”) such as α-bromoisocaproic acid to compound (1), toprovide Intermediate (8), where L is a leaving group such as bromo.Intermediate (8) is then reacted with a thiol or sulfur-containingnucleophilic reactant that contains the desired R⁵* group, for example,potassium thioacetate or thiourea.

If desired, pharmaceutically acceptable salts of the compounds offormula I can be prepared by contacting the free acid or base form of acompound of formula I with a pharmaceutically acceptable base or acid.

Scheme V: Pro-drug Synthesis

Prodrugs can be readily synthesized using the techniques describedabove. In addition, prodrugs can be formed by further modifying activecompounds of formula I where Ar**—COO represents Ar—R¹ and R⁵ is—C₀₋₃alkylene-SH, as shown below:

Thus, both prodrug A and prodrug C can be readily synthesized from thecorresponding active prodrug.

Certain intermediates described herein are believed to be novel andaccordingly, such compounds are provided as further aspects of theinvention including, for example, the compounds of formulas VIII, IX andX, and salts thereof:

Where Ar* is Ar—R¹*; Ar, r, Y, Z, Q, W, X, and R⁵⁻⁷ are as defined forformula I; and R¹* is selected from —C(O)O—P², —SO₂O—P⁵, —SO₂NH—P⁶,—P(O)(O—P⁷)₂, —OCH(CH₃)—C(O)O—P², —OCH(aryl)-C(O)O—P², andtetrazol-5-yl-P⁴; where P² is a carboxy-protecting group, P⁴ is atetrazole-protecting group, P⁵ is a hydroxyl-protecting group, P⁶ is asulfonamide-protecting group, and P⁷ is a phosphate-protecting group;

Where Ar, r, Y, Z, Q, W, X, and R⁶⁻⁷ are as defined for formula I; R⁵*is selected from —C₀₋₃alkylene-S—P³, —C₀₋₃alkylene-C(O)NH(O—P⁵),—C₀₋₃alkylene-N(O—P⁵)—C(O)R^(5d), —C₀₋₁alkylene-NHC(O)CH₂S—P³,—NH—C₀₋₁alkylene-P(O)(O—P⁷)₂, —C₀₋₃alkylene-P(O)(O—P⁷)—R^(5e),—C₀₋₂alkylene-CHR^(5f)—C(O)O—P² and—C₀₋₃alkylene-C(O)NR^(5g)—CHR^(5h)—C(O)O—P²; and R^(5d-h) are as definedfor formula I; where P² is a carboxy-protecting group, P³ is athiol-protecting group, P⁵ is a hydroxyl-protecting group, and P⁷ is aphosphate-protecting group; and

Where Ar* is Ar—R¹*; Ar, r, Y, Z, Q, W, X, and R⁶⁻⁷ are as defined forformula I; R¹* is selected from —C(O)O—P², —SO₂O—P⁵, —SO₂NH—P⁶,—P(O)(O—P⁷)₂, —OCH(CH₃)—C(O)O—P², —OCH(aryl)-C(O)O—P², andtetrazol-5-yl-P⁴; R⁵* is selected from is selected from—C₀₋₃alkylene-S—P³, —C₀₋₃alkylene-C(O)NH(O—P⁵),—C₀₋₃alkylene-N(O—P⁵)—C(O)R^(5d), —C₀₋₁alkylene-NHC(O)CH₂S—P³,—NH—C₀₋₁alkylene-P(O)(O—P⁷)₂, —C₀₋₃alkylene-P(O)(O—P⁷)—R^(5e),—C₀₋₂alkylene-CHR^(5f)—C(O)O—P² and—C₀₋₃alkylene-C(O)NR^(59g)—CHR^(5h)—C(O)O—P²; and R^(5d-h) are asdefined for formula I; where P² is a carboxy-protecting group, P³ is athiol-protecting group, P⁴ is a tetrazole-protecting group, P⁵ is ahydroxyl-protecting group, P⁶ is a sulfonamide-protecting group, and P⁷is a phosphate-protecting group. Thus, another method of preparingcompounds of the invention involves deprotecting a compound of formulaVIII, IX, or X.

Further details regarding specific reaction conditions and otherprocedures for preparing representative compounds of the invention orintermediates thereof are described in the Examples set forth below.

Utility

Compounds of the invention possess angiotensin II type 1 (AT₁) receptorantagonist activity. In one embodiment, compounds of the invention areselective for inhibition of the AT₁ receptor over the AT₂ receptor.Compounds of the invention also possess neprilysin (NEP) inhibitionactivity, that is, the compounds are able to inhibit enzyme-substrateactivity. In another embodiment, the compounds do not exhibitsignificant inhibitory activity of the angiotensin-converting enzyme.Compounds of formula I may be active drugs as well as prodrugs. Thus,when discussing the activity of compounds of the invention, it isunderstood that any such prodrugs have the expected activity oncemetabolized.

One measure of the affinity of a compound for the AT₁ receptor is theinhibitory constant (K₁) for binding to the AT₁ receptor. The pK, valueis the negative logarithm to base 10 of the K. One measure of theability of a compound to inhibit NEP activity is the inhibitoryconcentration (IC₅₀), which is the concentration of compound thatresults in half-maximal inhibition of substrate conversion by the NEPenzyme. The pIC₅₀ value is the negative logarithm to base 10 of theIC₅₀. Compounds of formula I and pharmaceutically acceptable saltsthereof that have both AT₁ receptor-antagonizing activity and NEPenzyme-inhibiting activity are of particular interest, including thosethat exhibit a pK, at the AT₁ receptor greater than or equal to about5.0, and exhibit a pIC₅₀ for NEP greater than or equal to about 5.0.

In one embodiment, compounds of interest have a pK_(i) at the AT₁receptor ≧about 6.0, a pK, at the AT₁ receptor ≧about 7.0, or a pK, atthe AT₁ receptor ≧about 8.0. Compounds of interest also include thosehaving a pIC₅₀ for NEP ≧about 6.0 or a pIC₅₀ for NEP ≧about 7.0. Inanother embodiment, compounds of interest have a pK_(i) at the AT₁receptor within the range of about 8.0-10.0 and a pIC₅₀ for NEP withinthe range of about 7.0-10.0.

In another embodiment, compounds of particular interest have a pK, forbinding to an AT₁ receptor greater than or equal to about 7.5 and a NEPenzyme pIC₅₀ greater than or equal to about 7.0. In another embodiment,compounds of interest have a pK, greater than or equal to about 8.0 anda pIC₅₀ greater than or equal to about 8.0.

It is noted that in some cases, compounds of the invention, while stillhaving dual activity, may possess either weak AT₁ receptor antagonistactivity or weak NEP inhibition activity. In such cases, those of skillin the art will recognize that these compounds still have utility asprimarily either a NEP inhibitor or a AT₁ receptor antagonist,respectively, or have utility as research tools.

Exemplary assays to determine properties of compounds of the invention,such as the AT₁ receptor binding and/or NEP inhibiting activity, aredescribed in the Examples and include by way of illustration and notlimitation, assays that measure AT₁ and AT₂ binding (described in Assay1), and NEP inhibition (described in Assay 2). Useful secondary assaysinclude assays to measure ACE inhibition (also described in Assay 2) andaminopeptidase P (APP) inhibition (described in Sulpizio et al. (2005)JPET 315:1306-1313). A pharmacodynamic assay to assess the in vivoinhibitory potencies for ACE, AT₁, and NEP in anesthetized rats isdescribed in Assay 3 (see also Seymour et al. Hypertension 7(SupplI):I-35-I-42, 1985 and Wigle et al. Can. J. Physiol. Pharmacol.70:1525-1528, 1992), where AT₁ inhibition is measured as the percentinhibition of the angiotensin II pressor response, ACE inhibition ismeasured as the percent inhibition of the angiotensin I pressorresponse, and NEP inhibition is measured as increased urinary cyclicguanosine 3′, 5′-monophosphate (cGMP) output. Useful in vivo assaysinclude the conscious spontaneously hypertensive rat (SHR) model, whichis a renin dependent hypertension model useful for measuring AT₁receptor blocking (described in Assay 4; see also Intengan et al. (1999)Circulation 100(22):2267-2275 and Badyal et al. (2003) Indian Journal ofPharmacology 35:349-362), and the conscious desoxycorticosteroneacetate-salt (DOCA-salt) rat model, which is a volume dependenthypertension model useful for measuring NEP activity (described in Assay5; see also Trapani et al. (1989) J. Cardiovasc. Pharmacol. 14:419-424,Intengan et al. (1999) Hypertension 34(4):907-913, and Badyal et al.(2003) supra). Both the SHR and DOCA-salt models are useful forevaluating the ability of a test compound to reduce blood pressure. TheDOCA-salt model is also useful to measure a test compound's ability toprevent or delay a rise in blood pressure. Compounds of the inventionare expected to antagonize the AT₁ receptor and/or inhibit the NEPenzyme in any of the assays listed above, or assays of a similar nature.Thus, the aforementioned assays are useful in determining thetherapeutic utility of compounds of the invention, for example, theirutility as antihypertensive agents. Other properties and utilities ofcompounds of the invention can be demonstrated using other in vitro andin vivo assays well-known to those skilled in the art.

Compounds of the invention are expected to be useful for the treatmentand/or prevention of medical conditions responsive to AT₁ receptorantagonism and/or NEP inhibition. Thus it is expected that patientssuffering from a disease or disorder that is treated by antagonizing theAT₁ receptor and/or by inhibiting the NEP enzyme can be treated byadministering a therapeutically effective amount of a compound of theinvention. For example, by antagonizing the AT₁ receptor and thusinterfering with the action of angiotensin II on its receptors, thesecompounds are expected to find utility in preventing the increase inblood pressure produced by angiotensin II, a potent vasopressor. Inaddition, by inhibiting NEP, the compounds are also expected topotentiate the biological effects of endogenous peptides that aremetabolized by NEP, such as the natriuretic peptides, bombesin,bradykinins, calcitonin, endothelins, enkephalins, neurotensin,substance P and vasoactive intestinal peptide. For example, bypotentiating the effects of the natriuretic peptides, compounds of theinvention are expected to be useful to treat glaucoma. These compoundsare also expected to have other physiological actions, for example, onthe renal, central nervous, reproductive and gastrointestinal systems.

Compounds of the invention are expected to find utility in treatingand/or preventing medical conditions such as cardiovascular and renaldiseases. Cardiovascular diseases of particular interest include heartfailure such as congestive heart failure, acute heart failure, chronicheart failure, and acute and chronic decompensated heart failure. Renaldiseases of particular interest include diabetic nephropathy and chronickidney disease. One embodiment of the invention is directed to a methodfor treating hypertension, comprising administering to a patient atherapeutically effective amount of a compound of the invention.Typically, the therapeutically effective amount is the amount that issufficient to lower the patient's blood pressure. In one embodiment, thecompound is administered as an oral dosage form.

Another embodiment of the invention is directed to a method for treatingheart failure, comprising administering to a patient a therapeuticallyeffective amount of a compound of the invention. Typically, thetherapeutically effective amount is the amount that is sufficient tolower blood pressure and/or improve renal functions. In one embodiment,the compound is administered as an intravenous dosage form. When used totreat heart failure, the compound may be administered in combinationwith other therapeutic agents such as diuretics, natriuretic peptides,and adenosine receptor antagonists.

Compounds of the invention are also expected to be useful inpreventative therapy, for example in preventing the progression ofcardiac insufficiency after myocardial infarction, preventing arterialrestenosis after angioplasty, preventing thickening of blood vesselwalls after vascular operations, preventing atherosclerosis, andpreventing diabetic angiopathy.

In addition, as NEP inhibitors, compounds of the invention are expectedto inhibit enkephalinase, which will inhibit the degradation ofendogenous enkephalins and thus such compounds may also find utility asanalgesics. Due to their NEP inhibition properties, compounds of theinvention are also expected to be useful as antitussive agents andantidiarrheal agents (for example, for the treatment of waterydiarrhea), as well as find utility in the treatment of menstrualdisorders, preterm labor, pre-eclampsia, endometriosis, reproductivedisorders (for example, male and female infertility, polycystic ovariansyndrome, implantation failure), and male and female sexual dysfunction,including male erectile dysfunction and female sexual arousal disorder.More specifically, the compounds of the invention are expected to beuseful in treating female sexual dysfunction, which is often defined asa female patient's difficulty or inability to find satisfaction insexual expression. This covers a variety of diverse female sexualdisorders including, by way of illustration and not limitation,hypoactive sexual desire disorder, sexual arousal disorder, orgasmicdisorder and sexual pain disorder. When used to treat such disorders,especially female sexual dysfunction, compounds of the invention may becombined with one or more of the following secondary agents: PDE5inhibitors, dopamine agonists, estrogen receptor agonists and/orantagonists, androgens, and estrogens.

The amount of the compound of the invention administered per dose or thetotal amount administered per day may be predetermined or it may bedetermined on an individual patient basis by taking into considerationnumerous factors, including the nature and severity of the patient'scondition, the condition being treated, the age, weight, and generalhealth of the patient, the tolerance of the patient to the active agent,the route of administration, pharmacological considerations such as theactivity, efficacy, pharmacokinetics and toxicology profiles of thecompound and any secondary agents being administered, and the like.Treatment of a patient suffering from a disease or medical condition(such as hypertension) can begin with a predetermined dosage or a dosagedetermined by the treating physician, and will continue for a period oftime necessary to prevent, ameliorate, suppress, or alleviate thesymptoms of the disease or medical condition. Patients undergoing suchtreatment will typically be monitored on a routine basis to determinethe effectiveness of therapy. For example, in treating hypertension,blood pressure measurements may be used to determine the effectivenessof treatment. Similar indicators for other diseases and conditionsdescribed herein, are well known and are readily available to thetreating physician. Continuous monitoring by the physician will insurethat the optimal amount of the compound of the invention will beadministered at any given time, as well as facilitating thedetermination of the duration of treatment. This is of particular valuewhen secondary agents are also being administered, as their selection,dosage, and duration of therapy may also require adjustment. In thisway, the treatment regimen and dosing schedule can be adjusted over thecourse of therapy so that the lowest amount of active agent thatexhibits the desired effectiveness is administered and, further, thatadministration is continued only so long as is necessary to successfullytreat the disease or medical condition.

Since compounds of the invention possess AT₁ receptor antagonistactivity and/or NEP enzyme inhibition activity, such compounds are alsouseful as research tools for investigating or studying biologicalsystems or samples having AT₁ receptors or a NEP enzyme, for example tostudy diseases where the AT₁ receptor or NEP enzyme plays a role. Anysuitable biological system or sample having AT₁ receptors and/or a NEPenzyme may be employed in such studies which may be conducted either invitro or in vivo. Representative biological systems or samples suitablefor such studies include, but are not limited to, cells, cellularextracts, plasma membranes, tissue samples, isolated organs, mammals(such as mice, rats, guinea pigs, rabbits, dogs, pigs, humans, and soforth), and the like, with mammals being of particular interest. In oneparticular embodiment of the invention an AT₁ receptor in a mammal isantagonized by administering an AT₁-antagonizing amount of a compound ofthe invention. In another particular embodiment, NEP enzyme activity ina mammal is inhibited by administering a NEP-inhibiting amount of acompound of the invention. Compounds of the invention can also be usedas research tools by conducting biological assays using such compounds.

When used as a research tool, a biological system or sample comprisingan AT₁ receptor and/or a NEP enzyme is typically contacted with an AT₁receptor-antagonizing or NEP enzyme-inhibiting amount of a compound ofthe invention. After the biological system or sample is exposed to thecompound, the effects of antagonizing the AT₁ receptor and/or inhibitingthe NEP enzyme are determined using conventional procedures andequipment, such as by measuring receptor binding in a binding assay ormeasuring ligand-mediated changes in a functional assay. Exposureencompasses contacting cells or tissue with the compound, administeringthe compound to a mammal, for example by i.p., i. v. or s.c.administration, and so forth. This determining step can involvemeasuring a response (a quantitative analysis) or can involve making anobservation (a qualitative analysis). Measuring a response involves, forexample, determining the effects of the compound on the biologicalsystem or sample using conventional procedures and equipment, such asradioligand binding assays and measuring ligand-mediated changes infunctional assays. The assay results can be used to determine theactivity level as well as the amount of compound necessary to achievethe desired result, that is, an AT₁ receptor-antagonizing and/or a NEPenzyme-inhibiting amount. Typically, the determining step will involvedetermining the AT₁ receptor ligand-mediated effects and/or determiningthe effects of inhibiting the NEP enzyme.

Additionally, compounds of the invention can be used as research toolsfor evaluating other chemical compounds, and thus are also useful inscreening assays to discover, for example, new compounds having AT₁receptor-antagonizing activity and/or NEP-inhibiting activity. In thismanner, a compound of the invention is used as a standard in an assay toallow comparison of the results obtained with a test compound and withcompounds of the invention to identify those test compounds that haveabout equal or superior activity, if any. For example, K_(i) data (asdetermined, for example, by a binding assay) for a test compound or agroup of test compounds is compared to the K_(i) data for a compound ofthe invention to identify those test compounds that have the desiredproperties, for example, test compounds having a K_(i) value about equalor superior to a compound of the invention, if any. This aspect of theinvention includes, as separate embodiments, both the generation ofcomparison data (using the appropriate assays) and the analysis of testdata to identify test compounds of interest. Thus, a test compound canbe evaluated in a biological assay, by a method comprising the steps of:(a) conducting a biological assay with a test compound to provide afirst assay value; (b) conducting the biological assay with a compoundof the invention to provide a second assay value; wherein step (a) isconducted either before, after or concurrently with step (b); and (c)comparing the first assay value from step (a) with the second assayvalue from step (b). Exemplary biological assays include an AT₁ receptorbinding assay and a NEP enzyme inhibition assay.

Pharmaceutical Compositions and Formulations

Compounds of the invention are typically administered to a patient inthe form of a pharmaceutical composition or formulation. Suchpharmaceutical compositions may be administered to the patient by anyacceptable route of administration including, but not limited to, oral,rectal, vaginal, nasal, inhaled, topical (including transdermal),ocular, and parenteral modes of administration. Further, the compoundsof the invention may be administered, for example orally, in multipledoses per day (for example, two, three, or four times daily), in asingle daily dose or a single weekly dose. It will be understood thatany form of the compounds of the invention, (that is, free base, freeacid, pharmaceutically acceptable salt, solvate, etc.) that is suitablefor the particular mode of administration can be used in thepharmaceutical compositions discussed herein.

Accordingly, in one embodiment, the invention is directed to apharmaceutical composition comprising a pharmaceutically acceptablecarrier and a compound of the invention. The compositions may containother therapeutic and/or formulating agents if desired. When discussingcompositions, the “compound of the invention” may also be referred toherein as the “active agent,” to distinguish it from other components ofthe formulation, such as the carrier. Thus, it is understood that theterm “active agent” includes compounds of formula I as well aspharmaceutically acceptable salts, solvates and prodrugs of thatcompound.

The pharmaceutical compositions of the invention typically contain atherapeutically effective amount of a compound of the invention. Thoseskilled in the art will recognize, however, that a pharmaceuticalcomposition may contain more than a therapeutically effective amount,such as in bulk compositions, or less than a therapeutically effectiveamount, that is, individual unit doses designed for multipleadministration to achieve a therapeutically effective amount. Typically,the composition will contain from about 0.01-95 wt % of active agent,including, from about 0.01-30 wt %, such as from about 0.01-10 wt %,with the actual amount depending upon the formulation itself, the routeof administration, the frequency of dosing, and so forth. In oneembodiment, a composition suitable for an oral dosage form, for example,may contain about 5-70 wt %, or from about 10-60 wt % of active agent.

Any conventional carrier or excipient may be used in the pharmaceuticalcompositions of the invention. The choice of a particular carrier orexcipient, or combinations of carriers or excipients, will depend on themode of administration being used to treat a particular patient or typeof medical condition or disease state. In this regard, the preparationof a suitable composition for a particular mode of administration iswell within the scope of those skilled in the pharmaceutical arts.Additionally, carriers or excipients used in such compositions arecommercially available. By way of further illustration, conventionalformulation techniques are described in Remington: The Science andPractice of Pharmacy, 20^(th) Edition, Lippincott Williams & White,Baltimore, Md. (2000); and H. C. Ansel et al., Pharmaceutical DosageForms and Drug Delivery Systems, 7^(th) Edition, Lippincott Williams &White, Baltimore, Md. (1999).

Representative examples of materials which can serve as pharmaceuticallyacceptable carriers include, but are not limited to, the following:sugars, such as lactose, glucose and sucrose; starches, such as cornstarch and potato starch; cellulose, such as microcrystalline cellulose,and its derivatives, such as sodium carboxymethyl cellulose, ethylcellulose and cellulose acetate; powdered tragacanth; malt; gelatin;talc; excipients, such as cocoa butter and suppository waxes; oils, suchas peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil,corn oil and soybean oil; glycols, such as propylene glycol; polyols,such as glycerin, sorbitol, mannitol and polyethylene glycol; esters,such as ethyl oleate and ethyl laurate; agar; buffering agents, such asmagnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-freewater; isotonic saline; Ringer's solution; ethyl alcohol; phosphatebuffer solutions; compressed propellant gases, such aschlorofluorocarbons and hydrofluorocarbons; and other non-toxiccompatible substances employed in pharmaceutical compositions.

Pharmaceutical compositions are typically prepared by thoroughly andintimately mixing or blending the active agent with a pharmaceuticallyacceptable carrier and one or more optional ingredients. The resultinguniformly blended mixture may then be shaped or loaded into tablets,capsules, pills, canisters, cartridges, dispensers and the like usingconventional procedures and equipment.

In formulations where the compound of the invention contains a thiolgroup, additional consideration may be given to minimize or eliminateoxidation of the thiol to form a disulfide. In solid formulations, thismay be accomplished by reducing the drying time, decreasing the moisturecontent of the formulation, and including materials such as ascorbicacid, sodium ascorbate, sodium sulfite and sodium bisulfite, as well asmaterials such as a mixture of lactose and microcrystalline cellulose.In liquid formulations, stability of the thiol may be improved by theaddition of amino acids, antioxidants, or a combination of disodiumedetate and ascorbic acid.

In one embodiment, the pharmaceutical compositions are suitable for oraladministration. Suitable compositions for oral administration may be inthe form of capsules, tablets, pills, lozenges, cachets, dragees,powders, granules; solutions or suspensions in an aqueous or non-aqueousliquid; oil-in-water or water-in-oil liquid emulsions; elixirs orsyrups; and the like; each containing a predetermined amount of theactive agent.

When intended for oral administration in a solid dosage form (capsules,tablets, pills and the like), the composition will typically comprisethe active agent and one or more pharmaceutically acceptable carriers,such as sodium citrate or dicalcium phosphate. Solid dosage forms mayalso comprise: fillers or extenders, such as starches, microcrystallinecellulose, lactose, sucrose, glucose, mannitol, and/or silicic acid;binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and/or acacia; humectants, such as glycerol;disintegrating agents, such as agar-agar, calcium carbonate, potato ortapioca starch, alginic acid, certain silicates, and/or sodiumcarbonate; solution retarding agents, such as paraffin; absorptionaccelerators, such as quaternary ammonium compounds; wetting agents,such as cetyl alcohol and/or glycerol monostearate; absorbents, such askaolin and/or bentonite clay; lubricants, such as talc, calciumstearate, magnesium stearate, solid polyethylene glycols, sodium laurylsulfate, and/or mixtures thereof; coloring agents; and buffering agents.

Release agents, wetting agents, coating agents, sweetening, flavoringand perfuming agents, preservatives and antioxidants may also be presentin the pharmaceutical compositions. Exemplary coating agents fortablets, capsules, pills and like, include those used for entericcoatings, such as cellulose acetate phthalate, polyvinyl acetatephthalate, hydroxypropyl methylcellulose phthalate, methacrylicacid-methacrylic acid ester copolymers, cellulose acetate trimellitate,carboxymethyl ethyl cellulose, hydroxypropyl methyl cellulose acetatesuccinate, and the like. Examples of pharmaceutically acceptableantioxidants include: water-soluble antioxidants, such as ascorbic acid,cysteine hydrochloride, sodium bisulfate, sodium metabisulfate sodiumsulfite and the like; oil-soluble antioxidants, such as ascorbylpalmitate, butylated hydroxyanisole, butylated hydroxytoluene, lecithin,propyl gallate, alpha-tocopherol, and the like; and metal-chelatingagents, such as citric acid, ethylenediamine tetraacetic acid, sorbitol,tartaric acid, phosphoric acid, and the like.

Compositions may also be formulated to provide slow or controlledrelease of the active agent using, by way of example, hydroxypropylmethyl cellulose in varying proportions or other polymer matrices,liposomes and/or microspheres. In addition, the pharmaceuticalcompositions of the invention may contain opacifying agents and may beformulated so that they release the active agent only, orpreferentially, in a certain portion of the gastrointestinal tract,optionally, in a delayed manner. Examples of embedding compositionswhich can be used include polymeric substances and waxes. The activeagent can also be in micro-encapsulated form, optionally with one ormore of the above-described excipients.

Suitable liquid dosage forms for oral administration include, by way ofillustration, pharmaceutically acceptable emulsions, microemulsions,solutions, suspensions, syrups and elixirs. Liquid dosage formstypically comprise the active agent and an inert diluent, such as, forexample, water or other solvents, solubilizing agents and emulsifiers,such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, oils (for example, cottonseed, groundnut, corn, germ, olive,castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethyleneglycols and fatty acid esters of sorbitan, and mixtures thereof.Suspensions may contain suspending agents such as, for example,ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitanesters, microcrystalline cellulose, aluminium metahydroxide, bentonite,agar-agar and tragacanth, and mixtures thereof.

When intended for oral administration, the pharmaceutical compositionsof the invention may be packaged in a unit dosage form. The term “unitdosage form” refers to a physically discrete unit suitable for dosing apatient, that is, each unit containing a predetermined quantity of theactive agent calculated to produce the desired therapeutic effect eitheralone or in combination with one or more additional units. For example,such unit dosage forms may be capsules, tablets, pills, and the like.

In another embodiment, the compositions of the invention are suitablefor inhaled administration, and will typically be in the form of anaerosol or a powder. Such compositions are generally administered usingwell-known delivery devices, such as a nebulizer, dry powder, ormetered-dose inhaler. Nebulizer devices produce a stream of highvelocity air that causes the composition to spray as a mist that iscarried into a patient's respiratory tract. An exemplary nebulizerformulation comprises the active agent dissolved in a carrier to form asolution, or micronized and combined with a carrier to form a suspensionof micronized particles of respirable size. Dry powder inhalersadminister the active agent as a free-flowing powder that is dispersedin a patient's air-stream during inspiration. An exemplary dry powderformulation comprises the active agent dry-blended with an excipientsuch as lactose, starch, mannitol, dextrose, polylactic acid,polylactide-co-glycolide, and combinations thereof. Metered-doseinhalers discharge a measured amount of the active agent usingcompressed propellant gas. An exemplary metered-dose formulationcomprises a solution or suspension of the active agent in a liquefiedpropellant, such as a chlorofluorocarbon or hydrofluoroalkane. Optionalcomponents of such formulations include co-solvents, such as ethanol orpentane, and surfactants, such as sorbitan trioleate, oleic acid,lecithin, glycerin, and sodium lauryl sulfate. Such compositions aretypically prepared by adding chilled or pressurized hydrofluoroalkane toa suitable container containing the active agent, ethanol (if present)and the surfactant (if present). To prepare a suspension, the activeagent is micronized and then combined with the propellant.Alternatively, a suspension formulation can be prepared by spray dryinga coating of surfactant on micronized particles of the active agent. Theformulation is then loaded into an aerosol canister, which forms aportion of the inhaler.

Compounds of the invention can also be administered parenterally (forexample, by subcutaneous, intravenous, intramuscular, or intraperitonealinjection). For such administration, the active agent is provided in asterile solution, suspension, or emulsion. Exemplary solvents forpreparing such formulations include water, saline, low molecular weightalcohols such as propylene glycol, polyethylene glycol, oils, gelatin,fatty acid esters such as ethyl oleate, and the like. Parenteralformulations may also contain one or more anti-oxidants, solubilizers,stabilizers, preservatives, wetting agents, emulsifiers, and dispersingagents. Surfactants, additional stabilizing agents or pH-adjustingagents (acids, bases or buffers) and anti-oxidants are particularlyuseful to provide stability to the formulation, for example, to minimizeor avoid hydrolysis of ester and amide linkages, or dimerization ofthiols that may be present in the compound. These formulations may berendered sterile by use of a sterile injectable medium, a sterilizingagent, filtration, irradiation, or heat. In one particular embodiment,the parenteral formulation comprises an aqueous cyclodextrin solution asthe pharmaceutically acceptable carrier. Suitable cyclodextrins includecyclic molecules containing six or more α-D-glucopyranose units linkedat the 1,4 positions by a linkages as in amylase, β-cyclodextrin orcycloheptaamylose. Exemplary cyclodextrins include cyclodextrinderivatives such as hydroxypropyl and sulfobutyl ether cyclodextrinssuch as hydroxypropyl-β-cyclodextrin and sulfobutyl etherβ-cyclodextrin. Exemplary buffers for such formulations includecarboxylic acid-based buffers such as citrate, lactate and maleatebuffer solutions.

Compounds of the invention can also be administered transdermally usingknown transdermal delivery systems and excipients. For example, thecompound can be admixed with permeation enhancers, such as propyleneglycol, polyethylene glycol monolaurate, azacycloalkan-2-ones and thelike, and incorporated into a patch or similar delivery system.Additional excipients including gelling agents, emulsifiers and buffers,may be used in such transdermal compositions if desired.

If desired, the compounds of the invention may be administered incombination with one or more other therapeutic agents. Thus, in oneembodiment, pharmaceutical compositions of the invention contain otherdrugs that are co-administered with a compound of the invention. Forexample, the composition may further comprise one or more drugs (alsoreferred to as “secondary agents(s)”) selected from the group ofdiuretics, β₁ adrenergic receptor blockers, calcium channel blockers,angiotensin-converting enzyme inhibitors, AT₁ receptor antagonists,neprilysin inhibitors, non-steroidal anti-inflammatory agents,prostaglandins, anti-lipid agents, anti-diabetic agents, anti-thromboticagents, renin inhibitors, endothelin receptor antagonists, endothelinconverting enzyme inhibitors, aldosterone antagonists,angiotensin-converting enzyme/neprilysin inhibitors, and combinationsthereof. Such therapeutic agents are well known in the art, and examplesare described below. By combining a compound of the invention with asecondary agent, triple therapy can be achieved; AT₁ receptor antagonistactivity, NEP inhibition activity, and activity associated with thesecondary agent (for example, β₁ adrenergic receptor blocker) can beachieved using only two active components. Since compositions containingtwo active components are typically easier to formulate thancompositions containing three active components, such two-componentcompositions provide a significant advantage over compositionscontaining three active components. Accordingly, in yet another aspectof the invention, a pharmaceutical composition comprises a compound ofthe invention, a second active agent, and a pharmaceutically acceptablecarrier. Third, fourth etc. active agents may also be included in thecomposition. In combination therapy, the amount of compound of theinvention that is administered, as well as the amount of secondaryagents, may be less than the amount typically administered inmonotherapy.

Compounds of the invention may be physically mixed with the secondactive agent to form a composition containing both agents; or each agentmay be present in separate and distinct compositions which areadministered to the patient simultaneously or at separate times. Forexample, a compound of the invention can be combined with a secondactive agent using conventional procedures and equipment to form acombination of active agents comprising a compound of the invention anda second active agent. Additionally, the active agents may be combinedwith a pharmaceutically acceptable carrier to form a pharmaceuticalcomposition comprising a compound of the invention, a second activeagent and a pharmaceutically acceptable carrier. In this embodiment, thecomponents of the composition are typically mixed or blended to create aphysical mixture. The physical mixture is then administered in atherapeutically effective amount using any of the routes describedherein.

Alternatively, the active agents may remain separate and distinct beforeadministration to the patient. In this embodiment, the agents are notphysically mixed together before administration but are administeredsimultaneously or at separate times as separate compositions. Suchcompositions can be packaged separately or may be packaged together in akit. When administered at separate times, the secondary agent willtypically be administered less than 24 hours after administration of thecompound of the invention, ranging anywhere from concurrent withadministration of the compound of the invention to about 24 hourspost-dose. This is also referred to as sequential administration. Thus,a compound of the invention can be orally administered simultaneously orsequentially with another active agent using two tablets, with onetablet for each active agent, where sequential may mean beingadministered immediately after administration of the compound of theinvention or at some predetermined time later (for example, one hourlater or three hours later). Alternatively, the combination may beadministered by different routes of administration, that is, one orallyand the other by inhalation.

In one embodiment, the kit comprises a first dosage form comprising acompound of the invention and at least one additional dosage formcomprising one or more of the secondary agents set forth herein, inquantities sufficient to carry out the methods of the invention. Thefirst dosage form and the second (or third, etc,) dosage form togethercomprise a therapeutically effective amount of active agents for thetreatment or prevention of a disease or medical condition in a patient.

Secondary agent(s), when included, are present in a therapeuticallyeffective amount such that they are typically administered in an amountthat produces a therapeutically beneficial effect when co-administeredwith a compound of the invention. The secondary agent can be in the formof a pharmaceutically acceptable salt, solvate, optically purestereoisomer, and so forth. The secondary agent may also be in the formof a prodrug, for example, a compound having a carboxylic acid groupthat has been esterified. Thus, secondary agents listed below areintended to include all such forms, and are commercially available orcan be prepared using conventional procedures and reagents.

In one embodiment, a compound of the invention is administered incombination with a diuretic. Representative diuretics include, but arenot limited to: carbonic anhydrase inhibitors such as acetazolamide anddichlorphenamide; loop diuretics, which include sulfonamide derivativessuch as acetazolamide, ambuside, azosernide, bumetanide, butazolamide,chloraminophenamide, clofenamide, clopamide, clorexolone, disulfamide,ethoxolamide, furosemide, mefruside, methazolamide, piretanide,torsemide, tripamide, and xipamide, as well as non-sulfonamide diureticssuch as ethacrynic acid and other phenoxyacetic acid compounds such astienilic acid, indacrinone and quincarbate; osmotic diuretics such asmannitol; potassium-sparing diuretics, which include aldosteroneantagonists such as spironolactone, and Na⁺ channel inhibitors such asamiloride and triamterene; thiazide and thiazide-like diuretics such asalthiazide, bendroflumethiazide, benzylhydrochlorothiazide,benzthiazide, buthiazide, chlorthalidone, chlorothiazide,cyclopenthiazide, cyclothiazide, epithiazide, ethiazide, fenquizone,flumethiazide, hydrochlorothiazide, hydroflumethiazide, indapamide,methylclothiazide, meticrane, metolazone, paraflutizide, polythiazide,quinethazone, teclothiazide, and trichloromethiazide; and combinationsthereof. In a particular embodiment, the diuretic is selected fromamiloride, bumetanide, chlorothiazide, chlorthalidone, dichlorphenamide,ethacrynic acid, furosemide, hydrochlorothiazide, hydroflumethiazide,indapamide, methylclothiazide, metolazone, torsemide, triamterene, andcombinations thereof. The diuretic will be administered in an amountsufficient to provide from about 5-50 mg per day, more typically 6-25 mgper day, with common dosages being 6.25 mg, 12.5 mg or 25 mg per day.

Compounds of the invention may also be administered in combination witha β₁ adrenergic receptor blocker. Representative β₁ adrenergic receptorblockers include, but are not limited to, acebutolol, alprenolol,amosulalol, arotinolol, atenolol, befunolol, betaxolol, bevantolol,bisoprolol, bopindolol, bucindolol, bucumolol, bufetolol, bufuralol,bunitrolol, bupranolol, bubridine, butofilolol, carazolol, carteolol,carvedilol, celiprolol, cetamolol, cloranolol, dilevalol, epanolol,esmolol, indenolol, labetolol, levobunolol, mepindolol, metipranolol,metoprolol such as metoprolol succinate and metoprolol tartrate,moprolol, nadolol, nadoxolol, nebivalol, nipradilol, oxprenolol,penbutolol, perbutolol, pindolol, practolol, pronethalol, propranolol,sotalol, sufinalol, talindol, tertatolol, tilisolol, timolol,toliprolol, xibenolol, and combinations thereof. In one particularembodiment, the adrenergic receptor blocker is selected from atenolol,bisoprolol, metoprolol, propranolol, sotalol, and combinations thereof.

In one embodiment, a compound of the invention is administered incombination with a calcium channel blocker. Representative calciumchannel blockers include, but are not limited to, amlodipine, anipamil,aranipine, barnidipine, bencyclane, benidipine, bepridil, clentiazem,cilnidipine, cinnarizine, diltiazem, efonidipine, elgodipine, etafenone,felodipine, fendiline, flunarizine, gallopamil, isradipine, lacidipine,lercanidipine, lidoflazine, lomerizine, manidipine, mibefradil,nicardipine, nifedipine, niguldipine, niludipine, nilvadipine,nimodipine, nisoldipine, nitrendipine, nivaldipine, perhexyline,prenylamine, ryosidine, semotiadil, terodiline, tiapamil, verapamil, andcombinations thereof. In a particular embodiment, the calcium channelblocker is selected from amlodipine, bepridil, diltiazem, felodipine,isradipine, lacidipine, nicardipine, nifedipine, niguldipine,niludipine, nimodipine, nisoldipine, ryosidine, verapamil, andcombinations thereof.

Compounds of the invention can also be administered in combination withan angiotensin-converting enzyme (ACE) inhibitor. Representative ACEinhibitors include, but are not limited to, accupril, alacepril,benazepril, benazeprilat, captopril, ceranapril, cilazapril, delapril,enalapril, enalaprilat, fosinopril, fosinoprilat, imidapril, lisinopril,moexipril, monopril, moveltopril, pentopril, perindopril, quinapril,quinaprilat, ramipril, ramiprilat, saralasin acetate, spirapril,temocapril, trandolapril, zofenopril, and combinations thereof. In aparticular embodiment, the ACE inhibitor is selected from: benazepril,enalapril, lisinopril, ramipril, and combinations thereof.

In one embodiment, a compound of the invention is administered incombination with an AT₁ receptor antagonist, also known as angiotensinII type 1 receptor blockers (ARBs). Representative ARBs include, but arenot limited to, abitesartan, benzyllosartan, candesartan, candesartancilexetil, elisartan, embusartan, enoltasosartan, eprosartan, fonsartan,forasartan, glycyllosartan, irbesartan, isoteoline, losartan, medoximil,milfasartan, olmesartan, opomisartan, pratosartan, ripisartan,saprisartan, saralasin, sarmesin, tasosartan, telmisartan, valsartan,zolasartan, and combinations thereof. In a particular embodiment, theARB is selected from candesartan, eprosartan, irbesartan, losartan,olmesartan, irbesartan, saprisartan, tasosartan, telmisartan, andcombinations thereof. Exemplary salts include eprosartan mesylate,losartan potassium salt, and olmesartan medoxomil. Typically, the ARBwill be administered in an amount sufficient to provide from about 4-600mg per dose, with exemplary daily dosages ranging from 20-320 mg perday.

In another embodiment, a compound of the invention is administered incombination with a neprilysin (NEP) inhibitor. Representative NEPinhibitors include, but are not limited to: candoxatril; candoxatrilat;dexecadotril ((+)-N-[2(R)-(acetylthiomethyl)-3-phenylpropionyl]glycinebenzyl ester); CGS-24128(3-[3-(biphenyl-4-yl)-2-(phosphonomethylamino)propionamido]propionicacid); CGS-24592((S)-3-[3-(biphenyl-4-yl)-2-(phosphonomethylamino)propionamido]propionicacid); CGS-25155(N-[9(R)-(acetylthiomethyl)-10-oxo-1-azacyclodecan-2(S)-ylcarbonyl]-4(R)-hydroxy-L-prolinebenzyl ester); 3-(1-carbamoylcyclohexyl)propionic acid derivativesdescribed in WO 2006/027680 to Hepworth et al. (Pfizer Inc.); JMV-390-1(2(R)-benzyl-3-(N-hydroxycarbamoyl)propionyl-L-isoleucyl-L-leucine);ecadotril; phosphoramidon; retrothiorphan; RU-42827(2-(mercaptomethyl)-N-(4-pyridinyl)benzenepropionamide); RU-44004(N-(4-morpholinyl)-3-phenyl-2-(sulfanylmethyl)propionamide); SCH-32615((S)—N—[N-(1-carboxy-2-phenylethyl)-L-phenylalanyl]-β-alanine) and itsprodrug SCH-34826((S)—N—[N-[1-[[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]carbonyl]-2-phenylethyl]-L-phenylalanyl]-β-alanine);sialorphin; SCH-42495(N-[2(S)-(acetylsulfanylmethyl)-3-(2-methylphenyl)propionyl]-L-methionineethyl ester); spinorphin; SQ-28132(N-[2-(mercaptomethyl)-1-oxo-3-phenylpropyl]leucine); SQ-28603(N-[2-(mercaptomethyl)-1-oxo-3-phenylpropyl]-β-alanine); SQ-29072(7-[[2-(mercaptomethyl)-1-oxo-3-phenylpropyl]amino]heptanoic acid);thiorphan and its prodrug racecadotril; UK-69578(cis-4-[[[1-[2-carboxy-3-(2-methoxyethoxy)propyl]cyclopentyl]carbonyl]amino]cyclohexanecarboxylicacid); UK-447,841(2-{1-[3-(4-chlorophenyl)propylcarbamoyl]-cyclopentylmethyl}-4-methoxybutyricacid); UK-505,749((R)-2-methyl-3-{1-[3-(2-methylbenzothiazol-6-yl)propylcarbamoyl]cyclopentyl}propionicacid); 5-biphenyl-4-yl-4-(3-carboxypropionylamino)-2-methylpentanoicacid and 5-biphenyl-4-yl-4-(3-carboxypropionylamino)-2-methylpentanoicacid ethyl ester (WO 2007/056546); daglutril[(3S,2′R)-3-{1-[2′-(ethoxycarbonyl)-4′-phenylbutyl]-cyclopentan-1-carbonylamino}-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-aceticacid] described in WO 2007/106708 to Khder et al. (Novartis AG); andcombinations thereof. In a particular embodiment, the NEP inhibitor isselected from candoxatril, candoxatrilat, CGS-24128, phosphoramidon,SCH-32615, SCH-34826, SQ-28603, thiorphan, and combinations thereof. TheNEP inhibitor will be administered in an amount sufficient to providefrom about 20-800 mg per day, with typical daily dosages ranging from50-700 mg per day, more commonly 100-600 or 100-300 mg per day.

In yet another embodiment, a compound of the invention is administeredin combination with a non-steroidal anti-inflammatory agent (NSAID).Representative NSAIDs include, but are not limited to: acemetacin,acetyl salicylic acid, alclofenac, alminoprofen, amfenac, amiprilose,amoxiprin, anirolac, apazone, azapropazone, benorilate, benoxaprofen,bezpiperylon, broperamole, bucloxic acid, carprofen, clidanac,diclofenac, diflunisal, diftalone, enolicam, etodolac, etoricoxib,fenbufen, fenclofenac, fenclozic acid, fenoprofen, fentiazac, feprazone,flufenamic acid, flufenisal, fluprofen, flurbiprofen, furofenac,ibufenac, ibuprofen, indomethacin, indoprofen, isoxepac, isoxicam,ketoprofen, ketorolac, lofemizole, lornoxicam, meclofenamate,meclofenamic acid, mefenamic acid, meloxicam, mesalamine, miroprofen,mofebutazone, nabumetone, naproxen, niflumic acid, oxaprozin, oxpinac,oxyphenbutazone, phenylbutazone, piroxicam, pirprofen, pranoprofen,salsalate, sudoxicam, sulfasalazine, sulindac, suprofen, tenoxicam,tiopinac, tiaprofenic acid, tioxaprofen, tolfenamic acid, tolmetin,triflumidate, zidometacin, zomepirac, and combinations thereof. In aparticular embodiment, the NSAID is selected from etodolac,flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meloxicam,naproxen, oxaprozin, piroxicam, and combinations thereof.

In yet another embodiment, a compound of the invention is administeredin combination with an anti-lipid agent. Representative anti-lipidagents include, but are not limited to, statins such as atorvastatin,fluvastatin, lovastatin, pravastatin, rosuvastatin and simvastatin;cholesteryl ester transfer proteins (CETPs); and combinations thereof.

In yet another embodiment, a compound of the invention is administeredin combination with an anti-diabetic agent. Representative anti-diabeticagents include, but are not limited to: injectable drugs such as insulinand insulin derivatives; orally effective drugs including biguanidessuch as metformin, glucagon antagonists, α-glucosidase inhibitors suchas acarbose and miglitol, meglitinides such as repaglinide,oxadiazolidinediones, sulfonylureas such as chlorpropamide, glimepiride,glipizide, glyburide, and tolazamide, thiazolidinediones such aspioglitazone and rosiglitazone; and combinations thereof.

In one embodiment, a compound of the invention is administered incombination with an anti-thrombotic agent. Representativeanti-thrombotic agents include, but are not limited to, aspirin,anti-platelet agents, heparin, and combinations thereof. Compounds ofthe invention may also be administered in combination with a renininhibitor, examples of which include, but are not limited to, aliskiren,enalkiren, remikiren, and combinations thereof. In another embodiment, acompound of the invention is administered in combination with anendothelin receptor antagonist, representative examples of whichinclude, but are not limited to, bosentan, darusentan, tezosentan, andcombinations thereof. Compounds of the invention may also beadministered in combination with an endothelin converting enzymeinhibitor, examples of which include, but are not limited to,phosphoramidon, CGS 26303, and combinations thereof. In yet anotherembodiment, a compound of the invention is administered in combinationwith an aldosterone antagonist, representative examples of whichinclude, but are not limited to, eplerenone, spironolactone, andcombinations thereof.

Combined therapeutic agents may also be helpful in further combinationtherapy with compounds of the invention. For example, a combination ofthe ACE inhibitor enalapril (in the maleate salt form) and the diuretichydrochlorothiazide, which is sold under the mark Vaseretic®, or acombination of the calcium channel blocker amlodipine (in the besylatesalt form) and the ARB olmesartan (in the medoxomil prodrug form), or acombination of a calcium channel blocker and a statin, all may also beused with the compounds of the invention. Dual-acting agents may also behelpful in combination therapy with compounds of the invention. Forexample, angiotensin-converting enzyme/neprilysin (ACE/NEP) inhibitorssuch as: AVE-0848((4S,7S,12bR)-7-[3-methyl-2(S)-sulfanylbutyramido]-6-oxo-1,2,3,4,6,7,8,12b-octahydropyrido[2,1-a][2]benzazepine-4-carboxylicacid); AVE-7688 (ilepatril) and its parent compound; BMS-182657(2-[2-oxo-3(S)-[3-phenyl-2(S)-sulfanylpropionamido]-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]aceticacid); CGS-26303([N-[2-(biphenyl-4-yl)-1(S)-(1H-tetrazol-5-yl)ethyl]amino]methylphosphonicacid); CGS-35601(N-[1-[4-methyl-2(S)-sulfanylpentanamido]cyclopentylcarbonyl]-L-tryptophan);fasidotril; fasidotrilate; enalaprilat; ER-32935((3R,6S,9aR)-6-[3(S)-methyl-2(S)-sulfanylpentanamido]-5-oxoperhydrothiazolo[3,2-a]azepine-3-carboxylicacid); gempatrilat; MDL-101264((4S,7S,12bR)-7-[2(S)-(2-morpholinoacetylthio)-3-phenylpropionamido]-6-oxo-1,2,3,4,6,7,8,12b-octahydropyrido[2,1-a][2]benzazepine-4-carboxylicacid); MDL-101287([4S-[4α,7α(R*),12bβ]]-7-[2-(carboxymethyl)-3-phenylpropionamido]-6-oxo-1,2,3,4,6,7,8,12b-octahydropyrido[2,1-a][2]benzazepine-4-carboxylicacid); omapatrilat; RB-105(N-[2(S)-(mercaptomethyl)-3(R)-phenylbutyl]-L-alanine); sampatrilat;SA-898((2R,4R)—N-[2-(2-hydroxyphenyl)-3-(3-mercaptopropionyl)thiazolidin-4-ylcarbonyl]-L-phenylalanine);Sch-50690(N-[1(S)-carboxy-2-[N2-(methanesulfonyl)-L-lysylamino]ethyl]-L-valyl-L-tyrosine);and combinations thereof, may also be included. In one particularembodiment, the ACE/NEP inhibitor is selected from: AVE-7688,enalaprilat, fasidotril, fasidotrilate, omapatrilat, sampatrilat, andcombinations thereof.

Other therapeutic agents such as α₂-adrenergic receptor agonists andvasopressin receptor antagonists may also be helpful in combinationtherapy. Exemplary α₂-adrenergic receptor agonists include clonidine,dexmedetomidine, and guanfacine. Exemplary vasopressin receptorantagonists include tolvaptan.

The following formulations illustrate representative pharmaceuticalcompositions of the invention.

Exemplary Hard Gelatin Capsules for Oral Administration

A compound of the invention (50 g), 440 g spray-dried lactose and 10 gmagnesium stearate are thoroughly blended. The resulting composition isthen loaded into hard gelatin capsules (500 mg of composition percapsule). Alternately, a compound of the invention (20 mg) is thoroughlyblended with starch (89 mg), microcrystalline cellulose (89 mg) andmagnesium stearate (2 mg). The mixture is then passed through a No. 45mesh U.S. sieve and loaded into a hard gelatin capsule (200 mg ofcomposition per capsule).

Exemplary Gelatin Capsule Formulation for Oral Administration

A compound of the invention (100 mg) is thoroughly blended withpolyoxyethylene sorbitan monooleate (50 mg) and starch powder (250 mg).The mixture is then loaded into a gelatin capsule (300 mg of compositionper capsule).

Alternately, a compound of the invention (40 mg) is thoroughly blendedwith microcrystalline cellulose (Avicel PH 103; 260 mg) and magnesiumstearate (0.8 mg). The mixture is then loaded into a gelatin capsule(Size #1, White, Opaque) (300 mg of composition per capsule).

Exemplary Tablet Formulation for Oral Administration

A compound of the invention (10 mg), starch (45 mg) and microcrystallinecellulose (35 mg) are passed through a No. 20 mesh U.S. sieve and mixedthoroughly. The granules so produced are dried at 50-60° C. and passedthrough a No. 16 mesh U.S. sieve. A solution of polyvinylpyrrolidone (4mg as a 10% solution in sterile water) is mixed with sodiumcarboxymethyl starch (4.5 mg), magnesium stearate (0.5 mg), and talc (1mg), and this mixture is then passed through a No. 16 mesh U.S. sieve.The sodium carboxymethyl starch, magnesium stearate and talc are thenadded to the granules. After mixing, the mixture is compressed on atablet machine to afford a tablet weighing 100 mg.

Alternately, a compound of the invention (250 mg) is thoroughly blendedwith microcrystalline cellulose (400 mg), silicon dioxide fumed (10 mg),and stearic acid (5 mg). The mixture is then compressed to form tablets(665 mg of composition per tablet).

Alternately, a compound of the invention (400 mg) is thoroughly blendedwith cornstarch (50 mg), croscarmellose sodium (25 mg), lactose (120mg), and magnesium stearate (5 mg). The mixture is then compressed toform a single-scored tablet (600 mg of composition per tablet).

Alternately, a compound of the invention (100 mg) is thoroughly blendedwith cornstarch (100 mg) with an aqueous solution of gelatin (20 mg).The mixture is dried and ground to a fine powder Microcrystallinecellulose (50 mg) and magnesium stearate (5 mg) are the admixed with thegelatin formulation, granulated and the resulting mixture compressed toform tablets (100 mg of active per tablet).

Exemplary Suspension Formulation for Oral Administration

The following ingredients are mixed to form a suspension containing 100mg of active agent per 10 mL of suspension:

Ingredients Amount Compound of the invention 1.0 g Fumaric acid 0.5 gSodium chloride 2.0 g Methyl paraben 0.15 g Propyl paraben 0.05 gGranulated sugar 25.5 g Sorbitol (70% solution) 12.85 g Veegum ® K(magnesium aluminum silicate) 1.0 g Flavoring 0.035 mL Colorings 0.5 mgDistilled water q.s. to 100 mL

Exemplary Liquid Formulation for Oral Administration

A suitable liquid formulation is one with a carboxylic acid-based buffersuch as citrate, lactate and maleate buffer solutions. For example, acompound of the invention (which may be pre-mixed with DMSO) is blendedwith a 100 mM ammonium citrate buffer and the pH adjusted to pH 5, orwith is blended with a 100 mM citric acid solution and the pH adjustedto pH 2. Such solutions may also include a solubilizing excipient suchas a cyclodextrin, for example the solution may include 10 wt %hydroxypropyl-β-cyclodextrin.

Other suitable formulations include a 5% NaHCO₃ solution, with orwithout cyclodextrin.

Exemplary Injectable Formulation for Administration by Injection

A compound of the invention (0.2 g) is blended with 0.4 M sodium acetatebuffer solution (2.0 mL). The pH of the resulting solution is adjustedto pH 4 using 0.5 N aqueous hydrochloric acid or 0.5 N aqueous sodiumhydroxide, as necessary, and then sufficient water for injection isadded to provide a total volume of 20 mL. The mixture is then filteredthrough a sterile filter (0.22 micron) to provide a sterile solutionsuitable for administration by injection.

Exemplary Compositions for Administration by Inhalation

A compound of the invention (0.2 mg) is micronized and then blended withlactose (25 mg). This blended mixture is then loaded into a gelatininhalation cartridge. The contents of the cartridge are administeredusing a dry powder inhaler, for example.

Alternately, a micronized compound of the invention (10 g) is dispersedin a solution prepared by dissolving lecithin (0.2 g) in demineralizedwater (200 mL). The resulting suspension is spray dried and thenmicronized to form a micronized composition comprising particles havinga mean diameter less than about 1.5 μm. The micronized composition isthen loaded into metered-dose inhaler cartridges containing pressurized1,1,1,2-tetrafluoroethane in an amount sufficient to provide about 10 μgto about 500 μg of the compound of the invention per dose whenadministered by the inhaler.

Alternately, a compound of the invention (25 mg) is dissolved in citratebuffered (pH 5) isotonic saline (125 mL). The mixture is stirred andsonicated until the compound is dissolved. The pH of the solution ischecked and adjusted, if necessary, to pH 5 by slowly adding aqueous 1Nsodium hydroxide. The solution is administered using a nebulizer devicethat provides about 10 μg to about 500 μg of the compound of theinvention per dose.

EXAMPLES

The following Preparations and Examples are provided to illustratespecific embodiments of the invention. These specific embodiments,however, are not intended to limit the scope of the invention in any wayunless specifically indicated.

The following abbreviations have the following meanings unless otherwiseindicated and any other abbreviations used herein and not defined havetheir standard, generally accepted meaning:

-   -   ACE angiotensin converting enzyme    -   APP aminopeptidase P    -   AT₁ angiotensin II type 1 (receptor)    -   AT₂ angiotensin II type 2 (receptor)    -   BSA bovine serum albumin    -   DCM dichloromethane or methylene chloride    -   DIPEA N,N-diisopropylethylamine    -   DMAP 4-dimethylaminopyridine    -   DMF N,N-dimethylformamide    -   DMSO dimethyl sulfoxide    -   Dnp 2,4-dinitrophenyl    -   DOCA deoxycorticosterone acetate    -   EDC N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide    -   EDTA ethylenediaminetetraacetic acid    -   EGTA ethylene glycol bis(β-aminoethyl        ether)-N,N,N′N′-tetraacetic acid    -   EtOAc ethyl acetate    -   HATU N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium        hexafluorophosphate    -   Mca (7-methoxycoumarin-4-yl)acyl    -   MeCN acetonitrile    -   MeOH methanol    -   NaBH₃CN sodium cyanoborohydride    -   NBS N-bromosuccinimide    -   NEP neprilysin (EC 3.4.24.11)    -   PBS phosphate buffered saline    -   SHR spontaneously hypertensive rat    -   TFA trifluoroacetic acid    -   THF tetrahydrofuran    -   Tris tris(hydroxymethyl)aminomethane    -   Tween-20 polyethylene glycol sorbitan monolaurate

Unless noted otherwise, all materials, such as reagents, startingmaterials and solvents, were purchased from commercial suppliers (suchas Sigma-Aldrich, Fluka Riedel-de Haën, and the like) and were usedwithout further purification.

Reactions were run under nitrogen atmosphere, unless noted otherwise.The progress of reactions were monitored by thin layer chromatography(TLC), analytical high performance liquid chromatography (anal. HPLC),and mass spectrometry, the details of which are given in specificexamples. Solvents used in analytical HPLC were as follows: solvent Awas 98% water/2% MeCN/1.0 mL/L TFA; solvent B was 90% MeCN/10% water/1.0mL/L TFA.

Reactions were worked up as described specifically in each preparationor example; commonly reaction mixtures were purified by extraction andother purification methods such as temperature-, and solvent-dependentcrystallization, and precipitation. In addition, reaction mixtures wereroutinely purified by preparative HPLC, typically using Microsorb C18and Microsorb BDS column packings and conventional eluents.Characterization of reaction products was routinely carried out by massand ¹H-NMR spectrometry. For NMR measurement, samples were dissolved indeuterated solvent (CD₃OD, CDCl₃, or DMSO-d₆), and ¹H-NMR spectra wereacquired with a Varian Gemini 2000 instrument (400 MHz) under standardobservation conditions. Mass spectrometric identification of compoundswas typically conducted using an electrospray ionization method (ESMS)with an Applied Biosystems (Foster City, Calif.) model API 150 EXinstrument or an Agilent (Palo Alto, Calif.) model 1200 LC/MSDinstrument.

Preparation 1 4-Methylpentanoyl Chloride

Isocaproic acid (10.0 g, 86.1 mmol) was dissolved in methylene chloride(30.0 mL, 468.0 mmol), and thionyl chloride (18.8 mL, 258 mmol) wasadded. The mixture was stirred at room temperature overnight, thenrotovaped to provide the title compound, which was used immediately inthe next reaction.

Preparation 2 (S)-2-Acetylsulfanylmethyl-4-methylpentanoic Acid

(S)-4-Benzyl-3-(4-methylpentanoyl)oxazolidin-2-one (2a):(S)-4-Benzyl-2-oxazolidinone (15.1 g, 85.0 mmol) was dissolved in THF(200 mL, 2.5 mol), cooled at −78° C. under nitrogen, and stirred for 10minutes. 1.6 M of n-butyllithium in hexane (53.1 mL) was added dropwiseand stirred for 15 minutes. 4-Methylpentanoyl chloride (12.6 g, 93.5mmol) was added dropwise, stirred for 30 minutes at −78° C., then warmedto 0° C. for 2 hours. 150 mL of saturated NaHCO₃ was added and themixture was warmed to room temperature for 30 minutes. The mixture wasextracted with DCM, washed with Na₂CO₃ (5%) and saturated aqueous NaCl,dried over MgSO₄, filtered and concentrated. Excess oxazolidinone wasremoved using hexanes to provide intermediate (2a) (14.5 g).

(S)-4-Benzyl-3-((R)-2-hydroxymethyl-4-methylpentanoyl)oxazolidin-2-one(2b): Intermediate (2a) (14.5 g, 46.3 mmol) was dissolved in DCM (151mL, 2.4 mol) and stirred at 0° C. under nitrogen. 1 M titaniumtetrachloride in DCM (48.6 mL) was added and stirred for 15 minutes.DIPEA (8.9 mL, 51.0 mmol) was added dropwise at 0° C. and the mixturewas stirred for 75 minutes. 1,3,5-Trioxane (4.6 g, 51.0 mmol) in DCM (30mL) was then added. After 10 minutes a second equivalent of 1 M titaniumtetrachloride in DCM (48.6 mL) was added and the mixture stirred at 0°C. for 5 hours. The reaction was then quenched with 250 mL of saturatedammonium chloride. Water and DCM were added, and the aqueous phase wasextracted twice more with DCM. The organic layers were combined, driedover MgSO₄, filtered and concentrated. The resulting material waspurified by silica gel chromatography (0-60% EtOAc:hexanes) to provideintermediate (2b) (13.9 g).

(R)-2-Hydroxymethyl-4-methylpentanoic acid (2c): Intermediate (2b) (13.9g, 40.8 mmol) was dissolved in THF (200 mL, 2 mol) and stirred at 0° C.9 M hydrogen peroxide in water (46.3 mL) was added, followed by dropwiseaddition of 1.5 M lithium hydroxide monohydrate in water (54.4 mL). Themixture was then warmed to room temperature and stirred for 2.5 hours.Potassium hydroxide (4.6 g, 81.6 mmol) was added and the mixture washeated at 60° C. for 30 minutes and then cooled at room temperature. Tothis was added a solution of sodium sulfite (10 g in 200 mL water)followed by water and chloroform (200 mL of each). The aqueous layer wasextracted twice more with CHCl₃ (150 mL), acidified and extracted withEtOAc. The organic layer was then washed with saturated aqueous NaCl,dried over MgSO₄, filtered, and rotovaped to provide intermediate (2c)(5.4 g).

Triphenylphosphine (19.5 g, 74.3 mmol) was dissolved in THF (200 mL, 2mol) and cooled at 0° C. Diisopropyl azodicarboxylate (14.6 mL, 74.3mmol) was added dropwise and the mixture stirred for 10 minutes at 0° C.Intermediate (2c) (5.4 g, 37.1 mmol) and thioacetic acid (8.0 mL, 111mmol) were dissolved in THF (20 mL) and added dropwise to the reaction.After the addition, the mixture was removed from the ice bath andstirred at room temperature. The mixture was stirred for 3.5 hours,concentrated to approximately a third of the volume, and thenpartitioned between EtOAc and saturated NaHCO₃. The organic layer wasextracted three times more with saturated NaHCO₃ and the combinedaqueous extracts were washed twice with CHCl₃, acidified with 1N HCl andextracted three times with EtOAc. The organic layer was washed withsaturated aqueous NaCl, dried over MgSO₄, filtered, and rotovaped toprovide the title compound (33% yield).

Preparation 3 4′-Bromomethylbiphenyl-2-carboxylic Acid t-Butyl Ester

4′-Methylbiphenyl-2-carboxylic acid t-butyl ester (3a): A solution of4′-methylbiphenyl-2-carboxylic acid (48.7 g, 230 mmol) and thionylchloride (150 mL) was stirred at room temperature. After 5.5 hours, themixture was concentrated in vacuo. Excess thionyl chloride was removedby co-distillation with toluene to afford a yellow solid (52.6 g). Thematerial was then dissolved in THF (500 mL) and cooled to 0° C.Potassium t-butoxide (15.0 g, 130 mmol) was added portion wise, followedby addition of 1M solution of potassium t-butoxide in THF (250 mL).Additional solid potassium t-butoxide (21.4 g, 100 mmol) was added andthe mixture was stirred at 0° C. for 1.5 hours. The mixture was thenpartitioned between EtOAc and water, and the organic layer was washedwith saturated aqueous NaCl, dried over MgSO₄, filtered and concentratedto afford intermediate (3a) as a yellow oil (62.3 g), which was useddirectly in the next step.

Benzoyl peroxide (3.9 g, 16.0 mmol) was added to a solution ofintermediate (3a) (62 g, 230 mmol) and NBS (41.2 g, 230 mmol) in benzene(800 mL). The mixture was then heated at reflux. After 4.5 hours,benzoyl peroxide (1 g) was added, followed by NBS (16 g, 66.0 mmol) 30minutes later. The mixture was stirred for a total of 6 hours, cooled,filtered, and concentrated in vacuo. The resulting residue was thencrystallized from diethyl ether and hexane at 4° C. overnight to givethe title compound as a pale yellow solid (40.7 g). ¹H-NMR (DMSO): δ(ppm) 1.1 (s, 9H), 4.6 (s, 2H), 7.1-7.6 (m, 8H).

Preparation 4 4′-(5-Aminomethyl-2-butyl-4-chloroimidazol-1-ylmethyl)biphenyl-2-carboxylic Acid t-Butyl Ester

4′-(2-Butyl-4-chloro-5-formylimidazol-1-ylmethyl)biphenyl-2-carboxylicacid t-butyl ester (4a): 2-Butyl-5-chloro-3H-imidazole-4-carbaldehyde(9.9 g, 53.3 mmol), 4′-bromomethylbiphenyl-2-carboxylic acid t-butylester (18.5 g, 53.3 mmol), and K₂CO₃ (7.4 g, 53.3 mmol) were combined inDMF (200 mL) and stirred at room temperature overnight. The reaction wasquenched with water, extracted with EtOAc, washed with saturated aqueousNaCl, dried over MgSO₄, filtered and concentrated. The crude mixture waspurified by flash chromatography (0-40% EtOAc:hexanes) to yield 21.5 gof intermediate (4a).

4′-[2-Butyl-4-chloro-5-(hydroxyiminomethyl)imidazol-1-ylmethyl]biphenyl-2-carboxylicacid t-butyl ester (4b): Intermediate (4a) (12.1 g, 26.7 mmol) andNH₂OH.HCl (2.4 g, 34.7 mmol) were combined in 80 mL water and 160 mLpyridine and stirred at room temperature overnight. Water (80 mL) wasadded and the mixture was stirred for 1 hour. The precipitate wasfiltered and dried to yield 11.7 g of intermediate (4b), which was usedin the next step without further purification.

Intermediate (4b) (8.8 g, 19 mmol), NaBH₃CN (5.3 g, 84.6 mmol) andNH₄OAc (3.2 g, 41.4 mmol) were dissolved in MeOH (100 mL) and cooled to0° C. After 15 minutes, TiCl₃ (8.70 g, 56.4 mmol) was added in threeportions, and the mixture was stirred at 0° C. for 10 minutes. Themixture was then removed from the ice bath and allowed to warm to roomtemperature, while stirring, for 3 hours. The mixture was cooled to 0°C., the reaction quenched with NH₄OH (100 mL), and the mixture stirredfor 15 minutes. The resulting titanium salt precipitant was filtered offand rinsed with MeOH multiple times. The filtrate was concentrated. Theresulting residue was taken up in a 3:1 mixture of CHCl₃ andisopropanol. Saturated aqueous NaCl and saturated aqueous NaHCO₃ wereadded. The product was extracted twice with a 3:1 mixture of CHCl₃ andisopropanol, washed with saturated aqueous NaCl, dried over MgSO₄,filtered and concentrated to yield 8.2 g of the title compound.

Example 14′-5-[((S)-2-Acetylsulfanylmethyl-4-methylpentanoylamino)methyl]-2-butyl-4-chloroimidazol-1-ylmethylbiphenyl-2-carboxylicAcid t-Butyl Ester (1a; R^(1a)=t-butyl; R^(5a)=—C(O)CH₃);4′-5-[((S)-2-Acetylsulfanylmethyl-4-methylpentanoylamino)methyl]-2-butyl-4-chloroimidazol-1-ylmethylbiphenyl-2-carboxylicAcid (1b; R^(1a)═H; R^(5a)=—C(O)CH₃); and4′-2-Butyl-4-chloro-5-[((S)-2-mercaptomethyl-4-methylpentanoylamino)methyl]imidazol-1-ylmethylbiphenyl-2-carboxylicAcid (1c; R^(1a)═H; R^(5a)═H)

(S)-2-Acetylsulfanylmethyl-4-methylpentanoic acid (371 mg, 1.8 mmol) andHATU (691 mg, 1.8 mmol) was dissolved in DMF (5 mL, 60 mmol) and stirredat room temperature for 15 minutes. DIPEA (0.3 mL, 2 mmol) was thenadded and the mixture was stirred for 1 hour.4′-(5-Aminomethyl-2-butyl-4-chloroimidazol-1-ylmethyl)biphenyl-2-carboxylicacid t-butyl ester (750 mg, 1.7 mmol) and DIPEA (0.3 mL, 2 mmol) in DMF(2 mL) was added and the mixture was stirred at room temperature for 4hours. The reaction was quenched with water and the mixture extractedwith EtOAc. The organic layer was washed with saturated aqueous NaCl,dried over MgSO₄, filtered and concentrated. The reaction was purifiedby silica gel chromatography (1:1 EtOAc:hexanes) to obtain theacetylsulfanyl ester intermediate (1a). This intermediate was dissolvedin DCM:TFA (1:1) (3 mL each) and stirred at room temperature for 3.5hours and then concentrated to obtain the acetylsulfanyl acidintermediate (1b). This intermediate was redissolved in 1:1 MeOH:NaOH(1N) (2 mL each) and was stirred at room temperature under nitrogen for1 hour, the reaction quenched with acetic acid, and the mixtureconcentrated. The resulting material was purified by preparative HPLC(30-70%) to yield 360 mg of the final product (1c). MS m/z: [M+H⁺] calcdfor C₂₉H₃₆ClN₃O₃S, 542.22. found, 542.4. ¹H-NMR (DMSO): 8.4 (1H, t),7.69 (1H, d), 7.53 (1H, t), 7.42 (1H, t), 7.33 (1H, d), 7.27 (2H, d),7.01 (2H, d), 5.23 (2H, s), 4.18 (2H, m), 2.35 (1H, m), 2.05 (1H, t),1.45 (2H, m) 1.38 (2H, m) 1.2 (3H, m), 0.77 (9H, m).

Preparation 5 (S)-2-Acetylsulfanyl-4-methylpentanoic Acid

(R)-2-Bromo-4-methylpentanoic acid (5a): D-Leucine (9.9 g, 75.2 mmol)was dissolved in 3.0 M of HBr in water (120 mL) and cooled to 0° C. Asolution of NaNO₂ (8.3 g, 120 mmol) in water (20 mL, 100 mmol) wasadded. The reaction was stirred at 0° C. for 2.5 hours and thenextracted twice with EtOAc, washed twice with saturated aqueous NaCl,dried over MgSO₄, filtered, and concentrated to afford 12.6 g ofintermediate (5a) as a pale yellow oil. This was taken on to the nextstep without further purification. ¹H-NMR (DMSO): 4.31 (1H, t), 1.75(2H, m) 1.65 (1H, m) 0.82 (6H, dd).

Intermediate (5a) (12.5 g, 64.1 mmol), potassium thioacetate (11.0 g,96.1 mmol), and DMF (100 mL, 1.0 mol) were combined and the mixturestirred at room temperature for 1 hour. Water (100 mL) was then added,and the mixture was extracted three times with EtOAc, washed twice withsaturated aqueous NaCl, dried over MgSO₄, filtered, and concentrated.The product was purified by silica gel chromatography (0-40%EtOAc:hexanes with 5% acetic acid) to yield 6.8 g of the title compoundas a pale yellow oil. ¹H-NMR (DMSO): 3.96 (1H, t), 2.45 (3H, s), 1.70(1H, m), 1.55 (1H, m), 1.42 (1H, m), 0.84 (61-1, dd).

Alternate Synthesis of Title Compound

(R)-2-Bromo-4-methylpentanoic acid (5a): While stirring, D-leucine (76.6g, 584 mmol, 1.0 eq) was dissolved into 920 mL of aq. 3.0 M HBr (2.8mol, 4.7 eq) and cooled to 0° C. A solution of NaNO₂ (64.5 g, 934 mmol,1.6 eq) in 200 mL water was slowly added over 20 minutes and the mixturewas stirred at 0° C. for 3 hours. The mixture was extracted 2× with 500mL EtOAc, washed with saturated aqueous NaCl, dried over MgSO₄,filtered, and concentrated under reduced pressure, to yield(R)-2-bromo-4-methylpentanoic acid as a yellow oil (103 g). ¹H-NMR(DMSO) δ (ppm): 0.9 (m, 6H), 1.6-1.7 (m, 1H), 1.7-1.9 (m, 2H), 4.3 (t,1H).

Intermediate (5a) (103 g, 528 mmol, 1.0 eq) was dissolved into 800 mLDMF and cooled to 0° C. Potassium thioacetate (90.5 g, 792 mmol, 1.5 eq)was added slowly and the mixture was allowed to slowly warm to roomtemperature. After 8 hours, the reaction was quenched with 600 mL water,extracted 3× with 500 mL EtOAc, washed with saturated aqueous NaCl anddried over MgSO₄. The organic was filtered and concentrated underreduced pressure producing the crude title compound as a brown oil. Thecrude product (85 g) was dissolved into 350 mL diisopropyl ether andchilled at 0° C. in ice. 1.0 eq. of diisopropyl amine was added slowlyand the resulting mixture was stirred for 1 hour. The solution wasfiltered and the solid was washed with 250 mL cold diisopropyl ether.The solid was then suspended in 500 mL EtOAc and washed with 900 mL 5%KHSO₄ (aq.). The organic was dried over MgSO₄ and concentrated underreduced pressure to yield the title compound as a yellow oil (39.6 g).¹H-NMR (CDCl₃) δ (ppm): 0.9 (m, 6H), 1.6 (m, 1H), 1.7 (m, 1H), 1.8 (m,1H), 2.3 (s, 3H), 4.2 (t, 1H).

Alternately, thioacetic acid (13.7 g, 180 mmol) and DMF (300 mL) werecombined, and the mixture cooled in an ice bath. Sodium carbonate (19.0g, 180 mmol) was added. After 30 minutes, Intermediate (5a) (33.4 g, 171mmol) in 20 mL DMF was added dropwise and the mixture was stirred at 0°C. to room temperature over 7 hours. The reaction was diluted with 200mL EtOAc and washed with 200 mL of a 1:1 saturated aqueous NaCl:1N HClsolution. The layers were separated and the aqueous phase was extractedagain with 200 mL EtOAc. The organics were combined, washed withsaturated aqueous NaCl, dried over MgSO4, filtered, and concentratedunder reduced pressure. The recovered oil was dissolved into diisopropylether (150 mL, 1.1 mol) and chilled at 0° C. Dicyclohexylamine (33.4 mL,168 mmol) was added dropwise and the solid was allowed to crash out ofsolution. After stirring for an additional 30 minutes the material wasfiltered and washed with 150 mL cold diisopropyl ether. The recoveredsolid (41 g) was suspended in 300 mL EtOAc. 500 mL of 5% KHSO₄ was addedand the layers were separated. The organic was washed with saturatedaqueous NaCl, dried over MgSO4, filtered, and concentrated under reducedpressure o yield the title compound as a yellow oil (20.7 g). ¹H NMR(CDCl₃) δ (ppm): 0.9 (m, 6H), 1.6 (m, 1H), 1.7 (m, 1H), 1.8 (m, 1H), 2.3(s, 3H), 4.2 (t, 1H).

Preparation 6 5-Bromo-2-butyl-3H-imidazole-4-carbaldehyde

2-Butyl-3H-imidazole-4-carbaldehyde (30.0 g, 197 mmol) was dissolved inDMF (220 mL, 2.8 mol). NBS (36.8 g, 207 mmol) was added and the mixturewas stirred at room temperature overnight. The mixture was thenconcentrated and taken up in EtOAc and water. The aqueous layer wasextracted three times with EtOAc, and the combined organic extractswashed with saturated aqueous NaCl, dried over MgSO₄, filtered, andconcentrated. The mixture was purified by silica gel chromatography(0-50% EtOAc:hexanes) to obtain 7.8 g of the title compound as a graysolid. MS m/z: [M+H⁺] calcd for C₈H₁₁BrN₂O, 232.09. found 233.0. ¹H-NMR(DMSO): 13.3 (1H, br), 9.48 (1H, s), 2.66 (2H, t), 1.59 (2H, m), 1.25(2H, m), 0.85 (3H, t).

Preparation 7 4-Bromomethyl-2,3-difluorobenzoic Acid Methyl Ester

2,3-Difluoro-4-methyl-benzoic acid methyl ester (7a):2,3-Difluoro-4-methyl-benzoic acid (10.0 g, 58.1 mmol) was dissolved inMeOH (200 mL, 6.0 mol) and sulfuric acid (1.00 mL, 19.0 mmol), and washeated at reflux overnight. The mixture was then cooled and concentratedunder reduced pressure. The resulting residue was taken up in EtOAc andwashed with saturated aqueous NaCl, dried over MgSO₄, filtered andconcentrated to yield 9.0 g of intermediate (7a) as a white solid.¹H-NMR (CDCl₃): 7.61 (1H, t), 7.00 (1H, t), 3.93 (3H, s), 2.35 (3H, s).

Intermediate (7a) (9.0 g, 48.4 mmol), NBS (8.6 g, 48.4 mmol), andbenzoyl peroxide (100 mg, 0.5 mmol) were dissolved in benzene (200 mL,2.0 mol) and the mixture was heated at reflux overnight. The mixture wasthen cooled and concentrated under reduced pressure. The resultingresidue was taken up in EtOAc and washed with water and saturatedaqueous NaCl, dried over MgSO₄, filtered and concentrated. The crudereaction was purified by silica gel chromatography (0-10% EtOAc:hexanes)to obtain 4.6 g of the title compound as a light yellow solid. MS m/z:[M+H⁺] calcd for C₉H₇BrF₂O₂, 266.05. found 267.1. ¹H-NMR (CDCl₃): 7.70(1H, t), 7.28 (1H, t), 4.48 (2H, s), 3.95 (3H, s).

Preparation 84-(5-Aminomethyl-2-butyl-imidazol-1-ylmethyl)-2,3-difluorobenzoic AcidMethyl Ester Dihydrochloride Salt

4-(4-Bromo-2-butyl-5-formyl-imidazol-1-ylmethyl)-2,3-difluorobenzoicacid methyl ester (8a): 4-bromomethyl-2,3-difluorobenzoic acid methylester (3.5 g, 13.2 mmol), 5-bromo-2-butyl-3H-imidazole-4-carbaldehyde(3.1 g, 13.2 mmol) and potassium carbonate (1.8 g, 13.2 mmol) werecombined and dissolved in DMF (20 mL, 300 mmol). The mixture was stirredat room temperature overnight. The mixture was then diluted with waterand extracted with EtOAc. The organic layer was washed with saturatedaqueous NaCl, dried over MgSO₄, filtered, and concentrated. The crudereaction was purified by silica gel chromatography (0-50% EtOAc:hexanes)to obtain 4.16 g of intermediate (8a) as a yellow solid. MS m/z: [M+H⁺]calcd for C₁₇H₁₇BrF₂N₂O₃, 416.23. found 417.1. ¹H-NMR (CDCl₃): 9.68 (1H,s), 7.64 (1H, t), 6.55 (1H, t), 5.64 (2H, s), 3.95 (3H, s), 2.63 (2H,t), 1.69 (2H, m), 1.36 (2H, m) 0.90 (3H, t).

4-[4-Bromo-2-butyl-5-(hydroxyiminomethyl)imidazol-1-ylmethyl]-2,3-difluorobenzoicacid methyl ester (8b): Intermediate (8a) (4.1 g, 10 mmol) was dissolvedin pyridine (20 mL, 200 mmol), and water (10 mL, 600 mmol). NH₂OH.HCl(898 mg, 12.9 mmol) was added and the mixture was stirred at roomtemperature overnight. The reaction was quenched by the addition ofwater (20 mL) and the mixture stirred for 20 minutes. The resultingsolid was filtered and dried to yield 3.6 g of intermediate (8b) as alight yellow solid. MS m/z: [M+H⁺] calcd for C₁₇H₁₈BrF₂N₃O₃, 431.24.found 432.2.

Intermediate (8b) (3.6 g, 8.2 mmol), palladium hydroxide (0.58 g, 4.1mmol), 1 M of HCl in water (16.5 mL), and MeOH (190 mL, 4.7 mol) werecombined. The mixture was degassed and then stirred under hydrogen for 4hours. The palladium was filtered and then the solute was concentratedto yield 3.3 g of the title compound as a yellow-orange solid. MS m/z:[M+H⁺] calcd for C₁₇H₂₁F₂N₃O₂, 338.16. found 338.2. ¹H-NMR (DMSO): 9.69(2H, br), 7.84 (1H, s), 7.67 (1H, m), 6.94 (1H, m) 5.80 (2H, s), 4.10(2H, d), 3.88 (3H, s), 2.98 (2H, t), 1.56 (2H, m), 1.29 (2H, m), 0.84(3H, t).

Example 24-{2-Butyl-5-[((S)-2-mercapto-4-methylpentanoylamino)methyl]-imidazol-1-ylmethyl}-2,3-difluorobenzoicAcid

(S)-2-Acetylsulfanyl-4-methylpentanoic acid (205 mg, 1.1 mmol) wasdissolved in DMF (8.1 mL, 104 mmol). HATU (409 mg, 1.1 mmol) and DIPEA(170 μL, 1.0 mmol) were added and the mixture was stirred at roomtemperature for 30 minutes.4-(5-Aminomethyl-2-butyl-imidazol-1-ylmethyl)-2,3-difluorobenzoic acidmethyl ester dihydrochloride salt (401 mg, 1.0 mmol) was dissolved inDMF (1 ml) with DIPEA (170 μL, 1.0 mmol) and added to the mixture. Themixture was stirred at room temperature for 2 hours. The reaction wasthen quenched with water, and the mixture extracted with EtOAc, washedwith saturated aqueous NaCl, dried over MgSO₄, filtered andconcentrated. The crude residue was then redissolved in 1:1 MeOH:NaOH (4mL) and stirred at room temperature under nitrogen for 1 hour. Thereaction was quenched with acetic acid and the mixture was concentrated.The product was purified by preparative HPLC (2-90%) to yield 108 mg ofthe title compound as a white solid. MS m/z: [M+H⁺] calcd forC₂₂H₂₉F₂N₃O₃S, 454.19. found 454.2. ¹H-NMR (DMSO): 8.44 (1H, t), 7.59(1H, t), 7.25 (1H, s), 6.62 (1H, t), 5.56 (2H, s), 4.24 (2H, m), 3.14(2H, q), 2.79 (2H, t), 2.72 (1H, d), 1.2-1.6 (7H, m), 0.78 (6H, d), 0.71(3H, d).

Preparation 92-Butyl-3-(4-methoxycarbonylbenzyl)-3H-imidazole-4-carboxylic Acid (TFASalt)

4-(4-Bromo-2-butyl-5-formyl-imidazol-1-ylmethyl)benzoic acid methylester (9a): 5-Bromo-2-butyl-3H-imidazole-4-carbaldehyde (38 g, 160 mmol)was dissolved in DMF (400 mL, 5 mol). Potassium carbonate (27 g, 200mmol) was added followed by methyl 4-bromomethylbenzoate (38 g, 160mmol) and the solution was stirred at room temperature overnight. Themixture was then concentrated and purified by silica gel chromatography(0-50% EtOAc:hexanes) to yield intermediate (9a) (32.2 g, 62.2 mmol). MSm/z: [M+H⁺] calcd for C₁₇H₁₉N₂O₃Br, 379.3. found 379.1. ¹H-NMR (400 Mz,CD₃OD) δ (ppm): 0.82 (t, 3H, J=5 Hz), 1.28 (m, 2H), 1.54 (q, 2H, J=5Hz), 2.70 (t, 2H, J=5 Hz), 5.69 (s, 2H), 7.15 (d, 2H, J=5 Hz), 7.96 (d,2H, J=5 Hz), 9.66 (s, 1H).

5-Bromo-2-butyl-3-(4-methoxycarbonylbenzyl)-3H-imidazole-4-carboxylicacid (9b): Intermediate (9a) (20 g, 50 mmol) was dissolved in 1-butanol(580 mL, 6.3 mol). To this was added 2.0 M 2-methyl-2-butene in THF (295mL), sodium dihydrogen phosphate (50.6 g, 422 mmol), and sodium chlorite(50.6 g, 559 mmol) in water (780 mL, 43 mol). The mixture was stirred atroom temperature overnight then extracted with 500 mL EtOAc and washedtwice with 250 mL of saturated sodium sulfite solution. The organicextract was dried over MgSO₄, concentrated, then purified by silica gelchromatography (0-50% EtOAc:hexanes) to yield intermediate (9b) (20 g,50 mol). MS m/z: [M+H⁺] calcd for C₁₇H₁₉N₂O₄Br, 395.3. found 397.2.¹H-NMR (400 Mz, CD₃OD): δ (ppm) 0.82 (t, 3H, J=5 Hz), 1.27 (m, 2H), 1.53(q, 2H, J=5 Hz), 2.64 (t, 2H, J=5 Hz), 5.71 (s, 2H), 7.10 (d, 2H, J=5Hz), 7.96 (d, 2H, J=5 Hz).

Intermediate (9b) (20 g, 50 mmol) was dissolved in MeOH (390 mL, 9.6mol). TFA (4.33 mL, 56.2 mmol) was added to solubilize the material. Themixture was degassed under nitrogen and palladium 10% on carbon wt (0.54g, 5 mmol) was added. The mixture was placed under hydrogen and stirredat room temperature for 4 hours. The mixture was then filtered through apad of Celite® and concentrated. The resulting residue was trituratedwith EtOAc and filtered to recover the title compound as a TFA salt(15.9 g, 36.9 mmol). MS m/z: [M+H⁺] calcd for C₁₇H₂₀N₂O₄, 316.4. found317.3. ¹H-NMR (400 Mz, CD₃OD): δ (ppm) 0.85 (t, 3H, J=5 Hz), 1.32 (m,2H), 1.55 (q, 2H, J=5 Hz), 2.96 (t, 2H, J=5 Hz), 5.92 (s, 2H), 7.26 (d,2H, J=5 Hz), 8.00 (d, 2H, J=5 Hz), 8.2 (s, 1H).

Example 34-{2-Butyl-5-[(R)-1-(3-chlorobenzyl)-2-hydroxycarbamoylethylcarbamoyl]imidazol-1-ylmethyl}benzoicAcid (TFA salt)

2-Butyl-3-(4-methoxycarbonylbenzyl)-3H-imidazole-4-carboxylic acid TFAsalt (2.7 g, 6.3 mmol) was dissolved in DMF (30 mL). The solution wasstirred at room temperature and pentafluorophenol (1.2 g, 6.3 mmol), EDC(1.2 g, 6.3 mmol), and DIPEA (1.1 mL, 6.3 mmol) were added. The solutionwas allowed to stir at room temperature overnight. To this was added(R)-3-amino-4-(3-chlorophenyl)butyric acid HCl salt (0.8 g, 6.3 mmol)and DIPEA (1.1 mL, 6.3 mmol), and the solution was stirred at 60° C. for4 hours. The crude reaction mixture was then allowed to cool to roomtemperature, concentrated under reduced pressure, then diluted withEtOAc. The organic solution was washed with 1M phosphoric acid, asaturated solution of NaCl, then dried over MgSO₄. After filtration, theorganic solution was concentrated under reduced pressure to afford thecrude acid.

The crude acid was then dissolved in DMF (30 mL). The solution wasstirred at room temperature and pentafluorophenol (1.2 g, 6.3 mmol), EDC(1.2 g, 6.3 mmol), and DIPEA (1.1 mL, 6.3 mmol) were added. Theresulting solution was allowed to stir at room temperature overnight. Tothis was added hydroxylamine HCl salt (450 mg, 6.3 mmol) and DIPEA (1.1mL, 6.3 mmol), and the solution was stirred at 40° C. for 4 hours. Thecrude reaction mixture was allowed to cool to room temperature,concentrated under reduced pressure, and diluted with EtOAc. The organiclayer was then washed with 1M phosphoric acid, a saturated solution ofNaCl, and then dried over MgSO₄. After filtration, the mixture wasconcentrated under reduced pressure to afford the crude hydroxamate.

The crude hydroxamate was dissolved in THF (10 mL) followed by additionof 1M NaOH (31.6 mL, 31.6 mmol). The mixture was stirred at 40° C. for 4hours and then acidified to pH 4 with 1 M HCl. The aqueous solution wasextracted three times with EtOAc, and the combined organic extracts wereconcentrated under reduced pressure to afford the crude material whichwas purified by reverse phase chromatography (1:1 water:MeCN with 0.1%TFA) to obtain the title compound as a TFA salt (279 mg, 0.23 mmol). MSm/z: [M+H⁺] calcd for C₂₆H₂₉ClN₄O₅, 513.18. found 513.5. ¹H-NMR (400 Mz,(CD₃)₂SO): δ (ppm) 0.74 (t, 3H, J=5 Hz), 1.18 (q, 2H, J=5 Hz), 1.41 (m,2H), 2.20 (d, 2H, J=5 Hz), 2.68 (m, 3H), 4.36 (m, 2H), 5.71 (m, 2H),7.11 (m, 5H, J=5 Hz), 7.86 (m, 2H), 8.00 (s, 1H), 8.59 (s, 1H).

Preparation 10 5-(4′-Bromomethylbiphenyl-2-yl)-1-trityl-1H-tetrazole

To a nitrogen-saturated suspension ofN-triphenylmethyl-5-[4′-methylbiphenyl-2-yl]tetrazole (10 g, 20.9 mmol)in DCM was added NBS (3.7 g, 20.9 mmol) and a catalytic amount ofbenzoyl peroxide (60 mg, 0.24 mmol). The mixture was stirred at refluxfor 15 hours. After cooling to room temperature, the precipitate wasfiltered and the organic solution was concentrated in vacuo. Silica gelchromatography (EtOAc:hexanes) gave the title compound as a white solid.¹H-NMR (400 MHz, DMSO-d₆): δ (ppm) 4.61 (s, 2H), 6.80 (d, 6H), 7.01 (d,2H), 7.24 (d, 2H), 7.28-7.35 (m, 9H), 7.43-7.45 (dd, 1H), 7.50-7.56 (td,1H), 7.58-7.60 (td, 1H), 7.77-7.79 (dd, 1H).

Preparation 11C-{2-Butyl-3-[2′-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-3H-imidazol-4-yl}methylamine.2[C₂HF₃O₂]

2-Butyl-5-chloro-3-[2′-(1-trityl-1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-3H-imidazole-4-carbaldehyde(11a): To a DMF (150 mL) solution of5-(4′-bromomethyl-biphenyl-2-yl)-1-trityl-1H-tetrazole (30 g, 53.8 mmol)was added 2-butyl-5-chloro-3H-imidazole-4-carbaldehyde (10 g, 53.8 mmol)and K₂CO₃ (7.4 g, 53.8 mmol). The mixture was stirred at roomtemperature overnight. EtOAc (500 mL) was added and the organic waswashed three times with a NaHCO₃ solution (200 mL) followed by saturatedaqueous NaCl (200 mL). Solvent was removed and purification was achievedby silica gel chromatography (50:50 EtOAc:hexanes) using an isocraticgradient to provide intermediate (11a) a white solid (41 g). MS m/z:[M+H⁺] calcd for C₄₁H₃₅ClN₆O, 663.26. found 663.4. ¹H-NMR (d₄-MeOH):0.83 (m, 3H), 1.26 (m, 2H), 1.53 (m, 2H), 2.53 (m, 2H), 5.56 (s, 2H),6.87-6.96 (m, 8H), 7.05 (m, 2H), 7.25-7.43 (m, 10H), 7.53-7.58 (m, 2H),7.84 (d, 1H), 9.73 (s, 1H).

{2-Butyl-5-chloro-3-[2′-(1-trityl-1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-3H-imidazol-4-yl}-methanol(11b): To an EtOH (500 mL) solution of intermediate (11a) (41.0 g, 61.8mmol) was added solid NaBH₄ (2.8 g, 74.1 mmol). The mixture was stirredat room temperature for 1 hour. After cooling to 0° C., the reaction wasquenched by dropwise addition of a 50/50 solution of acetic acid/wateruntil no effervescence was observed. EtOAc (500 mL) was added and theorganic was washed three times with saturated aqueous NaCl (100 mL).Solvent was removed and purification was achieved by silica gelchromatography (50:50 EtOAc:hexanes) using an isocratic gradient toprovide intermediate (11b) as a white solid (37 g). MS m/z: [M+H⁺] calcdfor C₄₁H₃₇ClN₆O, 665.28. found 665.3. ¹H-NMR (d₄-MeOH): 0.79 (m, 3H),1.20 (m, 2H), 1.46 (m, 2H), 2.45 (m, 2H), 4.30 (s, 2H), 5.19 (s, 2H),6.83-6.90 (m, 8H), 7.05 (d, 2H), 7.23-7.33 (m, 10H), 7.53 (m, 2H), 7.81(d, 1H).

Methanesulfonic acid2-butyl-5-chloro-3-[2′-(1-trityl-1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-3H-imidazol-4-ylmethylester (11c): To a DCM (200 mL) solution of intermediate (11b) (13.6 g,20.4 mmol), cooled to −78° C., was added methane sulfonyl chloride (6.3mL, 81.6 mmol). The mixture was stirred at −78° C. for 15 minutes. Asaturated NaHCO₃ solution (100 mL) and EtOAc (500 mL) were added to thecooled mixture, which was then allowed to reach room temperature. Theorganic was washed an additional three times with saturated aqueous NaCl(100 mL). After drying over sodium sulfate and filtration, the removalof solvent provided intermediate (11c) as a yellow oil (15 g) which wasused directly in the next step. MS m/z: [M+H⁺] calcd for C₄₂H₃₉ClN₆O₃S,743.26; due to the reactive nature of intermediate (11c), only themethanol substituted product was observed upon running a mass spectrumof the sample when dissolved in methanol; methanol substituted product[M+H⁺]=679.6.

5-[4′-(5-Azidomethyl-2-butyl-4-chloro-imidazol-1-ylmethyl)-biphenyl-2-yl]-1-trityl-1H-tetrazole(11d): To a dimethyl sulfoxide (100 mL) solution of intermediate (11c)(15 g, 20 mmol) was added sodium azide (3.9 g, 60 mmol). The mixture wasstirred at room temperature for 20 minutes. EtOAc (500 mL) and saturatedaqueous NaCl (100 mL) were added and the layers were separated,retaining the organic layer. The organic was washed an additional threetimes with saturated aqueous NaCl (100 mL). After drying over sodiumsulfate and filtration, the removal of solvent provided intermediate(11d) as a yellow solid (12 g), which was used directly in the nextstep. MS m/z: [M+H⁺] calcd for C₄₁H₃₆ClN₉, 690.29. found 690.5.

C-{2-Butyl-5-chloro-3-[2′-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-3H-imidazol-4-yl}methylamine.2[C₂HF₃O₂](11e): To a MeOH (150 mL) solution of intermediate (11d) (12 g, 17mmol), was added palladium on carbon (6.0 g; 10% Pd w/w). The solutionwas first degassed and backfilled with nitrogen gas (1 atm) followed byadditional degassing and backfilling with hydrogen gas (1 atm). Thesolution was then stirred at room temperature for 2-3 hours at which theazide reduction was 50% complete. Additional palladium on carbon (1.0 g;10% Pd w/w) was added and the solution stirred under hydrogen. After 1.5hours the reaction was complete, the mixture was degassed and backfilledwith nitrogen prior to filtration through Celite. The filtrate wasreduced to a volume of 50 mL. Into the filtrate was slowly added 6N HCl(150 mL) and the solution was stirred for 4 hours and then evaporated todryness. Purification was accomplished by preparative HPLC (reversephase) to provide intermediate (11e) as a white solid bis-TFA salt (4.0g). MS m/z: [M+H⁺] calcd for C₂₂H₂₄ClN₇, 422.19. found. 422.0. ¹H-NMR(d₄-MeOH): 0.89 (m, 3H), 1.35 (m, 2H), 1.59 (m, 2H), 2.88 (m, 2H), 4.20(s, 2H), 5.58 (s, 2H), 7.10 (d, 2H), 7.19 (d, 2H), 7.52-7.67 (m, 4H).

To a MeOH (195 mL) solution of intermediate (11e) (2.34 g, 5.5 mmol),was added 1N NaOH (58 mL) and palladium on carbon (1.9 g; 10% Pd w/w).The solution was first degassed and backfilled with nitrogen gas (1 atm)followed by additional degassing and backfilling with hydrogen gas (1atm). The solution was then stirred at room temperature for 2-3 hours.The solution was degassed and backfilled with nitrogen prior tofiltration through Celite. Into the filtrate was slowly added 1N HCl (58mL) and the neutralized solution was evaporated to dryness. Purificationwas accomplished by preparative HPLC (reverse phase) to provide thetitle compound as a white solid bis-TFA salt (1.90 g). MS m/z: [M+H⁺]calcd for C₂₂H₂₅N₇ 388.22. found 388.2. ¹H-NMR (d₄-MeOH): 0.91 (m, 3H),1.38 (m, 2H), 1.63 (m, 2H), 3.00 (m, 2H), 4.21 (s, 2H), 5.61 (s, 2H),7.10 (d, 2H), 7.19 (d, 2H), 7.52-7.67 (m, 4H), 7.74 (s, 1H).

Preparation 12 (R)-2-(2-Benzyloxycarbamoyl-3-phenypropionylamino)succinic Acid 1-Methyl Ester

2-Benzyl-N-benzyloxy-malonamic acid ethyl ester was prepared asdescribed in Fournie-Zaluski et al. (1985) J. Med. Chem.28(9):1158-1169).

2-Benzyl-N-benzyloxy-malonamic acid (12a): To a solution of the2-benzyl-N-benzyloxy-malonamic acid ethyl ester (19 g, 58.1 mmol)dissolved in a mixture of THF (70 mL) and MeOH (200 mL) was added asolution of NaOH (5.4 g, 135 mmol) in water (100 mL). The mixture wasstirred at room temperature for 24 hours, and evaporated to removevolatile organic solvents. The aqueous residue was diluted with water(200 mL), and washed with DCM (200 mL). The aqueous layer was saved andacidified to pH˜4 by adding concentrated HCl. The desired product wasprecipitated, washed with water, dissolved in acetone (200 mL), andevaporated to dryness, affording intermediate (12a) as a white solid(14.2 g). ¹H-NMR (CD₃OD, 300 MHz) δ (ppm) 7.20-7.06 (m, 5H), 4.60-4.56(d, 1H), 4.42-4.38 (d, 1H), 3.10-2.98 (m, 2H).

2-Benzyl-N-benzyloxy-malonamic acid 2,5-dioxo-pyrrolidin-1-yl ester(12b): Intermediate (12a) (0.5 g, 1.7 mmol) was added toN-hydroxysuccinimide (290 mg, 2.6 mmol) and EDC (320 mg, 1.7 mmol) anddissolved in MeCN (6 mL). The mixture was stirred overnight at roomtemperature and then partitioned between EtOAc and 10% aqueous citricacid. The organic layer was separated, washed with saturated aqueousNaCl, dried over MgSO₄, filtered and concentrated to provideintermediate (12b) as a foam (0.8 g, 2 mmol).

Intermediate (12b) (170 mg, 420 μmol) was dissolved in MeCN (4 mL) andH-D-Asp-OMe (0.09 g, 0.63 mmol) was added followed by solid NaHCO₃ (110mg, 1.3 mmol) and water (1 mL). The reaction was stirred at roomtemperature overnight and then partitioned with EtOAc and aqueous HCl(0.01 N). The organic layer was washed with saturated aqueous NaCl,dried over MgSO₄, filtered, concentrated, and then purified bypreparative HPLC to provide the title compound (80 mg, 190 μmol).

Example 4(R)—N-{2-Butyl-3-[2′-(2H-tetrazol-5-yl)biphenyl-4-ylmethyl]-3H-imidazol-4-ylmethyl}-2-(2-hydroxycarbamoyl-3-phenyl-propionylamino)succinamicAcid

(R)-2-(2-Benzyloxycarbamoyl-3-phenylpropionylamino)succinic acid1-methyl ester (70 mg, 160 μmol) was mixed with DMF (1 mL). To thissolution was added HATU (60 mg, 160 μmol) and the solution was stirredfor 20 minutes.{2-Butyl-3-[2′-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-3H-imidazol-4-yl}methylamine(60 mg, 160 μmol) was then added followed by triethylamine (70 μL, 480μmol). After approximately 5 hours the reaction was partitioned betweenEtOAc and 0.01 N HCl. The aqueous layer was separated and extracted withEtOAc and the combined organic layers were washed with saturated aqueousNaCl, dried over MgSO₄, filtered and concentrated to yield 140 mg of aclear oil. The resulting oil was dissolved in MeOH (10 mL) and 1 N NaOHwas added (0.5 mL). The mixture was then stirred at room temperatureovernight and then briefly heated to 45° C. for 90 minutes. The mixturewas then cooled and acetic acid (20 drops) was added followed by 10%palladium on carbon (25 mg) under an inert atmosphere. The reaction wasthen charged with hydrogen (1 atm) and stirred for 29 hours. Thesolution was then filtered, concentrated, and purified by preparativeHPLC (reverse phase) to give the title compound as the TFA salt (18 mg,20 μmmol). MS m/z: [M+H⁺] calcd for C₃₆H₃₉N₉O₆, 694.30. found 694.4.

Example 5

Following the procedures described in the examples above, andsubstituting the appropriate starting materials and reagents, compounds5-1 to 5-42, having the following formula where R is an optionalsubstituent, were also prepared:

Ex. R^(1a) R² —X R⁵ R⁶ R⁷ R 5-1  H Cl —C(O)NH—(CH₂)₆— —CH₂—CH— R6 and R7taken — NHC(O)— [CH₂—O—(CH₂)₂— together to form cyclohexylene-OCH₃]—COOH cyclopentyl NHC(O)— 5-2  H Cl —C(O)NH—(CH₂)₄— —CH₂—CH— R⁶ andR⁷ taken — NHC(O)— [CH₂—O—(CH₂)₂— together to form cyclohexylene-OCH₃]—COOH cyclopentyl NHC(O)— 5-3  H Cl —C(O)NH—(CH₂)₂— —CH₂—CH— R⁶ andR⁷ taken — NHC(O)— [CH₂—O—(CH₂)₂— together to form cyclohexylene-OCH₃]—COOH cyclopentyl NHC(O)— 5-4  H Cl —C(O)NH—(CH₂)₄— —SH benzyl H —NHC(O)— 5-5  H Cl —C(O)NH—(CH₂)₂— —C(O)N(OH)H benzyl H — NHC(O)—CH₂—NHC(O)— 5-6  H Cl —C(O)NH—(CH₂)₄— —C(O)N(OH)H benzyl H — NHC(O)—CH₂—NHC(O)— 5-6  H Cl —CH₂—NHC(O)— —CH₂SH benzyl H — (CH₂)₂—NHC(O)— 5-8  HCl —CH₂—NHC(O)— —SH benzyl H — (CH₂)₂—NHC(O)— 5-9  H Cl —CH₂—NHC(O)——CH₂—CH— R⁶ and R⁷ taken — (CH₂)₂—NHC(O)— [CH₂—O—(CH₂)₂— together toform cyclohexylene- OCH₃]—COOH cyclopentyl NHC(O)— 5-10 H Cl—CH₂-NHC(O)— —CH₂—CH— R⁶ and R⁷ taken — (CH₂)₄-NHC(O)— [CH₂—O—(CH₂)₂—together to form cyclohexylene- OCH₃]—COOH cyclopentyl NHC(O)— 5-11 H Cl—CH₂—NHC(O)— —CH₂—CH— R⁶ and R⁷ taken — (CH₂)₆—NHC(O)— [CH₂—O—(CH₂)₂—together to form cyclohexylene- OCH₃]—COOH cyclopentyl NHC(O)— 5-12 H Cl—CH₂—NHC(O)— —SH benzyl H — 5-13 H Cl —CH₂—NHC(O)— —SC(O)CH₃ —CH(CH₃) H— CH₂CH₃ 5-14 H H —CH₂—NHC(O)— —SH —CH(CH₃) H — CH₂CH₃ 5-15 H H—CH₂—NHC(O)— —C(O)N(OH)H —CH₂CH— H — (CH₃)₂ 5-16 H H —CH₂—NHC(O)——SC(O)CH₃ —CH₂CH— H — (CH₃)₂ 5-17 H Cl —CH₂—NHC(O)— —C(O)N(OH)H —CH(CH₃)H — CH₂CH₃ 5-18 H Cl —CH₂—NHC(O)— —C(O)N[OC(O) —CH₂CH— H — CH₃]H (CH₃)₂5-19 H H —C(O)NH— —CH₂C(O)— benzyl H — N(OH)H 5-20 H H —C(O)NH——CH₂C(O)— —CH₂CH— H — N(OH)H (CH₃)₂ 5-21 H H —CH₂—NHC(O)— —CH₂SH —CH₂CH—H — (CH₃)₂ 5-22 H Cl —CH₂—NHC(O)— —CH₂SH —CH₂CH— H — (CH₃)₂ 5-23 H H—CH₂—NHC(O)— —NHC(O)— —CH₂CH— H — CH₂SH (CH₃)₂ 5-24 H Cl —CH₂—NHC(O)——C(O)N(OH)H cyclopentyl H — 5-25 H H —CH₂—NHC(O)— —C(O)N(OH)Hcyclopentyl H — 5-26 H —CH₂— —C(O)NH— —CH₂C(O)— benzyl H — OH N(OH)H5-27 H Cl —CH₂—NHC(O)— —CH₂SH —CH₂— H — cyclopropyl 5-28 H Cl—CH₂—NHC(O)— —CH₂SH —CH₂CH— H — (CH₃)₂ 5-29 H Cl —CH₂—NHC(O)— —CH₂SHbenzyl H F 5-30 H Cl —CH₂—NHC(O)— —C(O)N(OH)H —CH₂CH— H F (CH₃)₂ 5-31—CH₃ Cl —CH₂—NHC(O)— —CH₂SH —CH₂CH— H — (CH₃)₂ 5-32 H Cl —CH₂—NHC(O)——CH₂SH —(CH₂)₃CH₃ H — 5-33 H Cl —CH₂—NHC(O)— —CH₂SH —(CH₂)₂— H —CH(CH₃)₂ 5-34 H Cl —CH₂—NHC(O)— —CH₂SH —CH(CH₃)— H — CH₂CH₃ 5-35 H Cl—CH₂—NHC(O)— —CH₂SH —CH₂— H — cyclopentyl 5-36 H Cl —CH₂—NHC(O)— —CH₂SH—CH₂— H — cyclohexyl 5-37 H Cl —CH₂—NHC(O)— —CH₂SH —CH₂— H — naphthyl5-38 H —CH₂— —CH₂—NHC(O)— —SH —CH₂CH— H — CH₃ (CH₃)₂ 5-39 H —CH₂——CH₂—NHC(O)— —CH₂SH —CH₂CH— H — CH₃ (CH₃)₂ 5-40 H cyclo- —CH₂—NHC(O)——CH₂SH —CH₂CH— H — propyl (CH₃)₂ 5-41 H cyclo- —CH₂—NHC(O)— —SH —CH₂— H— propyl cyclopropyl 5-42 H —O— —CH₂—NHC(O)— —CH₂SH —CH₂CH— H — CH₃(CH₃)₂

(5-1)4′-[2-butyl-5-(6-{[4-({1-[2-carboxy-3-(2-methoxyethoxy)propyl]cyclopentanecarbonyl}amino)cyclohexanecarbonyl]amino}hexylcarbamoyl)-4-chloroimidazol-1-ylmethyl]biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₄₈H₆₆ClN₅O₉, 892.46. found 892.2.

(5-2)4′-[2-butyl-5-(4-{[4-({1-[2-carboxy-3-(2-methoxyethoxy)propyl]cyclopentanecarbonyl}amino)cyclohexanecarbonyl]amino}butylcarbamoyl)-4-chloroimidazol-1-ylmethyl]biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₄₆H₆₂ClN₅O₉, 864.42. found 864.4.

(5-3)4′-[2-butyl-5-(2-{[4-({1-[2-carboxy-3-(2-methoxyethoxy)propyl]cyclopentanecarbonyl}amino)cyclohexanecarbonyl]-amino}-ethylcarbamoyl)-4-chloroimidazol-1-ylmethyl]biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₄₄H₅₈ClN₅O₉, 836.39. found 836.4.

(5-4) 4′-{2-butyl-4-chloro-5-[4-((S)-2-mercapto-3-phenylpropionylamino)butylcarbamoyl]imidazol-1-ylmethyl}biphenyl-2-carboxylic acid. MS m/z:[M+H⁺] calcd for C₃₅H₃₉ClN₄O₄S, 647.24. found 648.2.

(5-5)4′-(2-butyl-4-chloro-5-{2-[2-(2-hydroxycarbamoyl-3-phenylpropionylamino)acetylamino]ethylcarbamoyl}imidazol-1-ylmethyl)biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₆H₃₉ClN₆O₇, 703.26. found 704.2.

(5-6)4′-(2-butyl-4-chloro-5-{4-[2-(2-hydroxycarbamoyl-3-phenylpropionylamino)acetylamino]butylcarbamoyl}imidazol-1-ylmethyl)biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₈H₄₃ClN₆O₇, 731.29. found 732.2.

(5-7)4′-(5-{[3-(2-benzyl-3-mercapto-propionylamino)propionylamino]methyl}-2-butyl-4-chloroimidazol-1-ylmethyl)biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₅H₃₉ClN₄O₄S, 647.24. found 647.2.

(5-8) 4′-(2-butyl-4-chloro-5-{[3-((s)-2-mercapto3-phenylpropionylamino)propionylamino]methyl}-imidazol-1-ylmethyl)biphenyl-2-carboxylic acid.MS m/z: [M+H⁺] calcd for C₃₄H₃₇ClN₄O₄S, 633.22. found 633.2.

(5-9)4′-{2-butyl-5-[(3-{[4-({1-[2-carboxy-3-(2-methoxyethoxy)propyl]cyclopentanecarbonyl}amino)-cyclohexanecarbonyl]amino}propionylamino)methyl]-4-chloroimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₄₅H₆₀ClN₅O₉, 850.41. found 850.4.

(5-10)4′-{2-butyl-5-[(5-{[4-({1-[2-carboxy-3-(2-methoxyethoxy)propyl]cyclopentanecarbonyl}amino)cyclohexanecarbonyl]amino}pentanoylamino)methyl]-4-chloroimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₄₇H₆₄ClN₅O₉, 878.44. found 878.4.

(5-11)4′-{2-butyl-5-[(7-{[4-(1-[2-carboxy-3-(2-methoxyethoxy)propyl]cyclopentanecarbonyl}amino)cyclohexanecarbonyl]amino}heptanoylamino)methyl]-4-chloroimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₄₉H₆₈ClN₅O₉, 906.47. found 906.4.

(5-12)4′-{2-butyl-4-chloro-5-[((s)-2-mercapto-3-phenylpropionylamino)methyl]imidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₁H₃₂ClN₃O₃S, 562.19. found 562.3.

(5-13)4′-{5-[(2-acetylsulfanyl-3-methylpentanoylamino)methyl]-2-butyl-4-chloroimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₀H₃₆ClN₃O₄S, 570.21. found 570.3.

(5-14)4′-{2-butyl-5-[(2-mercapto-3-methylpentanoylamino)methyl]imidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₂₈H₃₅N₃O₃S, 494.24. found 494.2.

(5-15)4′-{2-butyl-5-[(2-hydroxycarbamoyl-4-methylpentanoylamino)methyl]imidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₂₉H₃₆N₄O₅, 521.27. found 521.2. ¹H-NMR(DMSO) 10.6 (1H, s), 8.28 (1H, t), 7.71 (1H, d), 7.56 (1H, t), 7.44 (1H,d), 7.41 (1H, d), 7.31 (3H, t), 7.15 (2H, d), 5.49 (2H, s), 4.24 (2H,d), 2.98 (1H, t), 2.89, 2H, t), 1.45, (5H, m), 1.2 (2H, q), 0.77 (9H,m).

(5-16)4′-{5-[(2-acetylsulfanyl-3-methylpentanoylamino)methyl]-2-butylimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₀H₃₇N₃O₄S, 536.25. found 536.5.

(5-17)4′-{2-butyl-4-chloro-5-[(2-hydroxycarbamoyl-4-methylpentanoylamino)methyl]imidazol-1-ylmethyl}biphenyl-2-carboxylic acid. MS m/z: [M+H⁺]calcd for C₂₉H₃₅ClN₄O₅, 555.23. found 555.4.

(5-18)4′-{5-[(2-acetoxycarbamoyl-4-methyl-pentanoylamino)-methyl]-2-butyl-4-chloroimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₁H₃₇ClN₄O₆, 597.24. found 597.2.

(5-19)4′-[2-butyl-5-(1-hydroxycarbamoylmethyl-2-phenylethylcarbamoyl)imidazol-1-ylmethyl]biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₂H₃₄N₄O₅, 555.25. found 556.4.

(5-20)4′-[2-butyl-5-(1-hydroxycarbamoylmethyl-3-methylbutylcarbamoyl)imidazol-1-ylmethyl]biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₂₉H₃₆N₄O₅, 521.27. found 522.4.

(5-21)4′-{2-butyl-5-[(2-mercaptomethyl-4-methylpentanoylamino)methyl]imidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₂₉H₃₇N₃O₃S, 508.26. found 508.2.

(5-22)4′-{2-butyl-4-chloro-5-[(2-mercaptomethyl-4-methylpentanoylamino)methyl]imidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₂₉H₃₆ClN₃O₃S, 542.22. found 542.4.¹H-NMR (DMSO) 8.4 (1H, t), 7.69 (1H, d), 7.53 (1H, t), 7.42 (1H, t),7.33 (1H, d), 7.27 (2H, d), 7.01 (2H, d), 5.23 (2H, s), 4.18 (2H, m),2.35 (1H, m), 2.05 (1H, t), 1.45 (2H, m) 1.38 (2H, m) 1.2 (3H, m), 0.77(9H, m).

(5-23)4′-(2-butyl-5-{[2-(2-mercapto-acetylamino)-4-methylpentanoylamino]methyl}imidazol-1-ylmethyl)biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₀H₃₈N₄O₄S, 551.26. found 551.3.

(5-24)4′-{2-butyl-4-chloro-5-[(2-cyclopentyl-2-hydroxycarbamoylacetylamino)methyl]imidazol-1-ylmethyl}biphenyl-2-carboxylic acid. MS m/z: [M+H⁺]calcd for C₃₀H₃₅ClN₄O₅, 567.23. found 567.3.

(5-25)4′-{2-butyl-5-[(2-cyclopentyl-2-hydroxycarbamoylacetylamino)methyl]imidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₀H₃₆N₄O₅, 533.27. found 533.3.

(5-26)4′-[2-butyl-5-(1-hydroxycarbamoylmethyl-2-pheny-ethylcarbamoyl)-4-hydroxymethylimidazol-1-ylmethyl]biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₃H₃₆N₄O₆, 585.26. found 585.2.

(5-27)4′-{2-butyl-4-chloro-5-[(2-cyclopropylmethyl-3-mercaptopropionylamino)methyl]imidazol-1-ylmethyl}biphenyl-2-carboxylic acid. MS m/z: [M+H⁺]calcd for C₂₉H₃₄ClN₃O₃S, 540.20. found 540.0.

(5-28)4′-{2-butyl-4-chloro-5-[((r)-2-mercaptomethyl-4-methylpentanoylamino)methyl]imidazol-1-ylmethyl}biphenyl-2-carboxylic acid. MS m/z: [M+H⁺]calcd for C₂₉H₃₆ClN₃O₃S, 542.22. found 542.4. ¹H-NMR (DMSO) 8.4 (1H, t),7.69 (1H, d), 7.53 (1H, t), 7.42 (1H, t), 7.33 (1H, d), 7.27 (2H, d),7.01 (2H, d), 5.23 (2H, s), 4.18 (2H, m), 2.35 (1H, m), 2.05 (1H, t),1.45 (2H, m) 1.38 (2H, m) 1.2 (3H, m), 0.77 (9H, m).

(5-29)4′-{5-[(2-benzyl-3-mercapto-propionylamino)methyl]-2-butyl-4-chloroimidazol-1-ylmethyl}-3-fluorobiphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₂H₃₃ClFN₃O₃S, 594.19. found 594.4.

(5-30)4′-{2-butyl-4-chloro-5-[(2-hydroxycarbamoyl-4-methylpentanoylamino)methyl]imidazol-1-ylmethyl}-3-fluorobiphenyl-2-carboxylic acid. MS m/z:[M+H⁺] calcd for C₂₉H₃₄ClFN₄O₅, 573.22. found 574.

(5-31)4′-{2-butyl-4-chloro-5-[((S)-2-mercaptomethyl-4-methylpentanoylamino)methyl]imidazol-1-ylmethyl}biphenyl-2-carboxylic acid methyl ester. MSm/z: [M+H⁺] calcd for C₃₀H₃₈ClN₃O₃S, 556.23. found 556.2.

(5-32)4′-{2-butyl-4-chloro-5-[(2-mercaptomethylhexanoylamino)methyl]imidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₂₉H₃₆ClN₃O₃S, 542.22. found 542.2.

(5-33)4′-{2-butyl-4-chloro-5-[(2-mercaptomethyl-5-methylhexanoylamino)methyl]imidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₀H₃₈ClN₃O₃S, 556.23. found 556.2.

(5-34)4′-{2-butyl-4-chloro-5-[(2-mercaptomethyl-3-methylpentanoylamino)methyl]imidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₂₉H₃₆ClN₃O₃S, 542.22. found 542.2.

(5-35)4′-{2-butyl-4-chloro-5-[(3-cyclopentyl-2-mercaptomethylpropionylamino)methyl]imidazol-1-ylmethyl}biphenyl-2-carboxylic acid. MS m/z: [M+H⁺]calcd for C₃₁H₃₈ClN₃O₃S, 568.23. found 568.2.

(5-36)4′-{2-butyl-4-chloro-5-[(3-cyclohexyl-2-mercaptomethylpropionylamino)methyl]imidazol-1-ylmethyl}biphenyl-2-carboxylic acid. MS m/z: [M+H⁺]calcd for C₃₂H₄₀ClN₃O₃S, 582.25. found 582.2.

(5-37)4′-{2-butyl-4-chloro-5-[(2-mercaptomethyl-3-naphthalen-1-ylpropionylamino)methyl]imidazol-1-ylmethyl}biphenyl-2-carboxylic acid. MS m/z: [M+H⁺]calcd for C₃₆H₃₆ClN₃O₃S, 626.22. found 626.2.

(5-38)4′-{2-butyl-4-ethyl-5-[((S)-2-mercapto-4-methylpentanoylamino)methyl]-imidazol-1-ylmethyl}-biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₀H₃₉N₃O₃S, 522.27. found 522.4.

(5-39)4′-{2-butyl-4-ethyl-5-[((S)-2-mercaptomethyl-4-methylpentanoylamino)methyl]-imidazol-1-ylmethyl}-biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₁H₄₁N₃O₃S, 536.29. found 536.4.

(5-40)4′-{2-butyl-4-cyclopropyl-5-[((S)-2-mercaptomethyl-4-methylpentanoylamino)methyl]-imidazol-1-ylmethyl}-biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₂H₄₁N₃O₃S, 548.29. found 548.4.

(5-41)4′-{2-butyl-4-cyclopropyl-5-[((S)-3-cyclopropyl-2-mercapto-propionylamino)methyl]-imidazol-1-ylmethyl}-biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₁H₃₇N₃O₃S, 532.26. found 532.2.

(5-42)4′-{2-butyl-5-[((R)-2-mercaptomethyl-4-methylpentanoylamino)methyl]-4-methoxy-imidazol-1-ylmethyl}-biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₀H₃₉N₃O₄S, 538.27. found 538.6.

Example 6

Following the procedures described in the examples above, andsubstituting the appropriate starting materials and reagents, compounds6-1 to 6-44, having the following formula, were also prepared:

Ex. R² —X R⁵ R⁶ R⁷ 6-1  Cl —CH₂—NHC(O)— —CH₂—CH— R⁶ and R⁷ takentogether cyclohexylene- [CH₂—O—(CH₂)₂—OC to form cyclopentyl NHC(O)—H₃]—COOH 6-2  Cl —C(O)NH—(CH₂)₂— —CH₂—CH— R⁶ and R⁷ taken togetherNHC(O)— [CH₂—O—(CH₂)₂—OC to form cyclopentyl cyclohexylene- H₃]—COOHNHC(O)— 6-3  Cl —C(O)NH—(CH₂)₄— —CH₂—CH— R⁶ and R⁷ taken togetherNHC(O)— [CH₂—O—(CH₂)₂—OC to form cyclopentyl cyclohexylene- H₃]—COOHNHC(O)— 6-4  Cl —C(O)NH—(CH₂)₆— —CH₂—CH— R⁶ and R⁷ taken togetherNHC(O)— [CH₂—O—(CH₂)₂—OC to form cyclopentyl cyclohexylene- H₃]—COOHNHC(O)— 6-5  Cl —C(O)NH—(CH₂)₄— —CH₂SH benzyl H NHC(O)— 6-6  Cl—C(O)NH—(CH₂)₄— —SH benzyl H NHC(O)— 6-7  Cl —CH₂—NHC(O)— —CH₂SH benzylH (CH₂)₂—NHC(O)— 6-8  Cl —CH₂—NHC(O)— —CH₂SH benzyl H (CH₂)₄—NHC(O)—6-9  Cl —CH₂—NHC(O)— —CH₂SH benzyl H (CH₂)₆—NHC(O)— 6-10 Cl—C(O)NH—(CH₂)₂— —C(O)NH— benzyl H C(O)N(OH)—CH₂— (CH₂COOH) 6-11 Cl—C(O)NH—(CH₂)₄— —C(O)N(OH)H benzyl H CH(COOH)— NHC(O)— 6-12 Cl—C(O)NH—(CH₂)₄— —CH₂SH benzyl H CH(COOH)— NHC(O)— 6-13 Cl —CH₂—C(O)NH——CH₂—CH— R⁶ and R⁷ taken together (CH₂)₂—NHC(O)— [CH₂—O—(CH₂)₂—OC toform cyclopentyl cyclohexylene- H₃]—COOH NHC(O)— 6-14 Cl —CH₂—NHC(O)——CH₂—CH— R⁶ and R⁷ taken together (CH₂)₄—NHC(O)— [CH₂—O—(CH₂)₂—OC toform cyclopentyl cyclohexylene- H₃]—COOH NHC(O)— 6-15 Cl —CH₂—N(OH)C(O)——CH₂—CH— R⁶ and R⁷ taken together cyclohexylene- [CH₂—O—(CH₂)₂—OC toform cyclopentyl NHC(O)— H₃]—COOH 6-16 Cl —C(O)NH—CH₂— —C(O)NH— R⁶ andR⁷ taken together CH(COOH)—CH₂— (CH₂COOH) to form cyclopentyl 6-17 Cl—CH₂—NHC(O)—CH₂— —C(O)N(OH)H benzyl H CH(COOH)— NHC(O)— 6-18 H—CH₂—NHC(O)—CH₂— —C(O)N(OH)H benzyl H CH(COOH)— NHC(O)— 6-19 Cl—CH₂—NHC(O)— —C(O)N(OH)H benzyl H (CH₂)₂—CH(COOH)— NHC(O)— 6-20 Cl—C(O)NH—CH₂— —C(O)NH—CH(CH₂— R⁶ and R⁷ taken together CH(COOH)—CH₂—phenyl- to form cyclopentyl OH)(COOH) 6-21 Cl —C(O)NH—(CH₂)₃——C(O)N(OH)H benzyl H CH(COOH)— NHC(O)— 6-22 Cl —C(O)NH—(CH₂)₂——C(O)N(OH)H benzyl H CH(COOH)— NHC(O)— 6-23 Cl —C(O)NH—(CH₂)₄— —CH₂SH—CH₂-biphenyl H CH(COOH)— NHC(O)— 6-24 Cl —C(O)NH—(CH₂)₄— —C(O)N(OH)H—CH₂-biphenyl H CH(COOH)— NHC(O)— 6-25 H —C(O)NH—(CH₂)₂— —C(O)N(OH)Hbenzyl H CH(COOH)— NHC(O)— 6-26 H —CH₂—NHC(O)—CH₂— —NH—CH₂——CH₂-biphenyl H CH(COOH)— P(O)(OH)₂ NHC(O)— 6-27 H —C(O)NH—(CH₂)₄——C(O)N(OH)H benzyl H CH(COOH)— NHC(O)— 6-28 H —CH₂—NHC(O)—CH₂— —C(O)NH₂benzyl H CH(COOH)— NHC(O)— 6-29 Cl —CH₂—NHC(O)— —SC(O)CH₃ benzyl H 6-30Cl —CH₂—NHC(O)— —CH₂SC(O)CH₃ —CH(CH₃)₂ H 6-31 Cl —CH₂—NHC(O)——C(O)N(OH)H —CH₂CH(CH₃)₂ H 6-32 Cl —C(O)NH— —CH₂C(O)N(OH)H benzyl H 6-33H —C(O)NH— —CH₂C(O)N(OH)H —CH₂CH(CH₃)₂ H 6-34 Cl —CH₂—NHC(O)— —CH₂SH—CH₂CH(CH₃)₂ H 6-35 H —C(O)NH— —CH₂C(O)N(OH)H benzyl H 6-36 H—CH₂—NHC(O)— —CH₂SH —CH₂CH(CH₃)₂ H 6-37 H —CH₂—NHC(O)— —C(O)N(OH)H—CH₂CH(CH₃)₂ H 6-38 Cl —CH₂—NHC(O)— —CH₂SH —CH₂CH(CH₃)₂ H 6-39 H—CH₂—NHC(O)— —CH₂SH —CH₂CH(CH₃)₂ H 6-40 H —C(O)NH— —CH₂C(O)N(OH)H2-trifluoro- H methylbenzyl 6-41 H —CH₂—NHC(O)— —CH₂SH —CH₂CH(CH₃)₂ H6-42 Cl —CH₂—NHC(O)— —CH₂SH —CH₂CH(CH₃)₂ H 6-43 H —C(O)NH— —CH₂SH—CH₂CH(CH₃)₂ H 6-44 Cl —CH₂—NHC(O)— —SH CH₂CH(CH₃)₂ H

(6-1)3-{1-[4-({2-butyl-5-chloro-3-[2′-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-3H-imidazol-4-ylmethyl}carbamoyl)cyclohexylcarbamoyl]cyclopentyl}-2-(2-methoxyethoxymethyl)propionicacid. MS m/z: [M+H⁺] calcd for C₄₂H₅₅ClN₈O₆, 803.39; found 803.0.

(6-2)3-(1-{4-[2-({2-butyl-5-chloro-3-[2′-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-3H-imidazole-4-carbonyl}-amino)-ethylcarbamoyl]-cyclohexylcarbamoyl}-cyclopentyl)-2-(2-methoxy-ethoxymethyl)-propionicacid. MS m/z: [M+H⁺] calcd for C₄₄H₅₈ClN₉O₇, 860.42. found 860.2.

(6-3)3-(1-{4-[4-({2-butyl-5-chloro-3-[2′-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-3H-imidazole-4-carbonyl}amino)butylcarbamoyl]cyclohexylcarbamoyl}cyclopentyl)-2-(2-methoxyethoxymethyl)propionicacid. MS m/z: [M+H⁺] calcd for C₄₆H₆₂ClN₉O₇, 888.45. found 888.4.

(6-4)3-(1-{4-[6-({2-butyl-5-chloro-3-[2′-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-3H-imidazole-4-carbonyl}amino)hexylcarbamoyl]cyclohexylcarbamoyl}cyclopentyl)-2-(2-methoxyethoxymethyl)propionicacid. MS m/z: [M+H⁺] calcd for C₄₈H₆₆ClN₉O₇, 916.48. found 916.4.

(6-5)2-butyl-5-chloro-3-[2′-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-3H-imidazole-4-carboxylicacid [4-(2-benzyl-3-mercaptopropionylamino)butyl]amide. MS m/z: [M+H⁺]calcd for C₃₆H₄₁ClN₈O₂S, 685.28. found 685.2.

(6-6)2-butyl-5-chloro-3-[2′-(2H-tetrazol-5-yl)biphenyl-4-ylmethyl]-3H-imidazole-4-carboxylicacid [4-((R)-2-mercapto-3-phenylpropionylamino)butyl]amide. MS m/z:[M+H⁺] calcd for C₃₅H₃₉ClN₈O₂S, 671.26. found 671.2.

(6-7)N-[2-({2-butyl-5-chloro-3-[2′-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-3H-imidazol-4-ylmethyl}carbamoyl)ethyl]-2-mercaptomethyl-3-phenylpropionamide.MS m/z: [M+H⁺] calcd for C₃₅H₃₉ClN₈O₂S, 671.26. found 671.2.

(6-8) 5-(2-mercaptomethyl-3-phenylpropionylamino)pentanoic acid{2-butyl-5-chloro-3-[2′-(1-tetrazol-5-yl)-biphenyl-4-ylmethyl]-3H-imidazol-4-ylmethyl}amide.MS m/z: [M+H⁺] calcd for C₃₇H₄₃ClN₈O₂S, 699.29. found 699.2.

(6-9) 7-(2-mercaptomethyl-3-phenylpropionylamino)heptanoic acid{2-butyl-5-chloro-3-[2′-(1-tetrazol-5-yl)-biphenyl-4-ylmethyl]-3H-imidazol-4-ylmethyl}amide.MS m/z: [M+H⁺] calcd for C₃₉H₄₇ClN₈O₂S, 727.32. found 727.2.

(6-10)[2-({[3-({2-butyl-5-chloro-3-[2′-(2H-tetrazol-5-yl)biphenyl-4-ylmethyl]-3H-imidazole-4-carbonyl}amino)propionyl]hydroxyamino}methyl)-3-phenylpropionylamino]aceticacid. MS m/z: [M+H⁺] calcd for C₃₇H₄₀ClN₉O₆, 742.28. found 742.2.

(6-11)(S)-6-({2-butyl-5-chloro-3-[2′-(2H-tetrazol-5-yl)biphenyl-4-ylmethyl]-3H-imidazole-4-carbonyl}amino)-2-(2-hydroxycarbamoyl-3-phenylpropionylamino)hexanoicacid. MS m/z: [M+H⁺] calcd for C₃₈H₄₂ClN₉O₆, 756.30. found 756.2.

(6-12)(S)-2-(2-benzyl-3-mercapto-propionylamino)-6-({2-butyl-5-chloro-3-[2′-(2H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-3H-imidazole-4-carbonyl}amino)hexanoicacid. MS m/z: [M+H⁺] calcd for C₃₈H₄₃ClN₈O₄S, 743.28. found 743.2.

(6-13)3-(1-{4-[2-({2-butyl-5-chloro-3-[2′-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-3H-imidazol-4-ylmethyl}carbamoyl)ethylcarbamoyl]cyclohexylcarbamoyl}cyclopentyl)-2-(2-methoxy-ethoxymethyl)propionicacid. MS m/z: [M+H⁺] calcd for C₄₅H₆₀ClN₉O₇, 874.43. found 874.6.

(6-14)3-(1-{4-[4-({2-butyl-5-chloro-3-[2′-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-3H-imidazol-4-ylmethyl}carbamoyl)butylcarbamoyl]cyclohexylcarbamoyl}cyclopentyl)-2-(2-methoxyethoxymethyl)propionicacid. MS m/z: [M+H⁺] calcd for C₄₇H₆₄ClN₉O₇, 902.46. found 902.5

(6-15)3-{1-[4-({2-butyl-5-chloro-3-[2′-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-3H-imidazol-4-ylmethyl}hydroxycarbamoyl)cyclohexylcarbamoyl]cyclopentyl}-2-(2-methoxyethoxymethyl)propionicacid. MS m/z: [M+H⁺] calcd for C₄₂H₅₅ClN₈O₇, 819.39. found 819.5.

(6-16)2-[({2-butyl-5-chloro-3-[2′-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-3H-imidazole-4-carbonyl}amino)methyl]-3-[1-(carboxymethylcarbamoyl)cyclopentyl]propionic acid. MS m/z: [M+H⁺] calcd for C₃₄H₃₉ClN₈O₆, 691.27. found692.2.

(6-17)(R)—N-{2-butyl-5-chloro-3-[2′-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-3H-imidazol-4-ylmethyl}-2-(2-hydroxycarbamoyl-3-phenylpropionylamino)succinamicacid. MS m/z: [M+H⁺] calcd for C₃₆H₃₈ClN₉O₆, 728.26. found 728.5.

(6-18)(S)—N-{2-butyl-3-[2′-(2H-tetrazol-5-yl)biphenyl-4-ylmethyl]-3H-imidazol-4-ylmethyl}-2-(2-hydroxycarbamoyl-3-phenylpropionylamino)succinamicacid. MS m/z: [M+H⁺] calcd for C₃₆H₃₉N₉O₆, 694.30. found 694.5.

(6-19)(R)-4-({2-butyl-5-chloro-3-[2′-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-3H-imidazol-4-ylmethyl}carbamoyl)-2-(2-hydroxycarbamoyl-3-phenylpropionylamino)butyricacid. MS m/z: [M+H⁺] calcd for C₃₇H₄₀ClN₉O₆, 742.28. found 742.5.

(6-20)2-[({2-butyl-5-chloro-3-[2′-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-3H-imidazole-4-carbonyl}amino)methyl]-3-{1-[(S)-1-carboxy-2-(4-hydroxyphenyl)ethylcarbamoyl]cyclopentyl}propionicacid. MS m/z: [M+H⁺] calcd for C₄₁H₄₅ClN₈O₇, 797.31. found 797.2.

(6-21)(S)-5-({2-butyl-5-chloro-3-[2′-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-3H-imidazole-4-carbonyl}amino)-2-(2-hydroxycarbamoyl-3-phenylpropionylamino)pentanoicacid. MS m/z: [M+H⁺] calcd for C₃₇H₄₀ClN₉O₆, 742.28. found 742.5.

(6-22)(S)-4-({2-butyl-5-chloro-3-[2′-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-3H-imidazole-4-carbonyl}amino)-2-(2-hydroxycarbamoyl-3-phenylpropionylamino)butyricacid. MS m/z: [M+H⁺] calcd for C₃₆H₃₈ClN₉O₆, 728.26. found 728.5.

(6-23)(S)-2-(2-biphenyl-4-ylmethyl-3-mercaptopropionylamino)-6-({2-butyl-5-chloro-3-[2′-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-3H-imidazole-4-carbonyl}amino)hexanoic acid. MS m/z: [M+H⁺] calcd for C₄₄H₄₇ClN₈O₄S, 819.31. found819.7.

(6-24)(S)-2-(3-biphenyl-4-yl-2-hydroxycarbamoylpropionylamino)-6-({2-butyl-5-chloro-3-[2′-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-3H-imidazole-4-carbonyl}amino)hexanoic acid. MS m/z: [M+H⁺] calcd for C₄₄H₄₆ClN₉O₆, 832.33. found832.7.

(6-25)(S)-4-({2-butyl-3-[2′-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-3H-imidazole-4-carbonyl}amino)-2-(2-hydroxycarbamoyl-3-phenylpropionylamino)butyricacid. MS m/z: [M+H⁺] calcd for C₃₆H₃₉N₉O₆, 694.30. found 694.5.

(6-26)(S)-2-[(S)-3-biphenyl-4-yl-2-(phosphonomethylamino)propionylamino]-N-{2-butyl-3-[2′-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-3H-imidazol-4-ylmethyl}succinamicacid. MS m/z: [M+H⁺] calcd for C₄₂H₄₆N₉O₇P, 820.33. found 820.3.

(6-27)(S)-6-({2-butyl-3-[2′-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-3H-imidazole-4-carbonyl}amino)-2-(2-hydroxycarbamoyl-3-phenylpropionylamino)hexanoicacid. MS m/z: [M+H⁺] calcd for C₃₈H₄₃N₉O₆, 722.33. found 722.3.

(6-28)(R)—N-{2-butyl-3-[2′-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-3H-imidazol-4-ylmethyl}-2-(2-carbamoyl-3-phenylpropionylamino)succinamicacid. MS m/z: [M+H⁺] calcd for C₃₆H₃₉N₉O₅, 678.31. found 679.4.

(6-29) thioacetic acidS-[1-({2-butyl-5-chloro-3-[2′-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-3H-imidazol-4-ylmethyl}carbamoyl)-2-phenylethyl]ester.MS m/z: [M+H⁺] calcd for C₃₃H₃₄ClN₇O₂S, 628.22. found 628.5.

(6-30) thioacetic acidS-[2-({2-butyl-5-chloro-3-[2′-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-3H-imidazol-4-ylmethyl}carbamoyl)-3-methylbutyl]ester.MS m/z: [M+H⁺] calcd for C₃₀H₃₆ClN₇O₂S, 594.23. found 594.5.

(6-31)N-{2-butyl-5-chloro-3-[2′-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-3H-imidazol-4-ylmethyl}-N′-hydroxy-2-isobutylmalonamide.MS m/z: [M+H⁺] calcd for C₂₉H₃₅ClN₈O₃, 579.25. found 579.4.

(6-32)2-butyl-5-chloro-3-[2′-(2H-tetrazol-5-yl)biphenyl-4-ylmethyl]-3H-imidazole-4-carboxylicacid (1-hydroxycarbamoylmethyl-2-phenylethyl)amide. MS m/z: [M+H⁺] calcdfor C₃₂H₃₃ClN₈O₃, 613.24. found 614.4.

(6-33)2-butyl-3-[2′-(2H-tetrazol-5-yl)biphenyl-4-ylmethyl]-3H-imidazole-4-carboxylicacid (1-hydroxycarbamoylmethyl-3-methylbutyl)amide. MS m/z: [M+H⁺] calcdfor C₂₉H₃₆N₈O₃, 545.29. found 545.4.

(6-34) 2-mercaptomethyl-4-methylpentanoic acid{2-butyl-5-chloro-3-[2′-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-3H-imidazol-4-ylmethyl}amide.MS m/z: [M+H⁺] calcd for C₂₉H₃₆ClN₇OS, 566.24. found 566.4.

(6-35)2-butyl-3-[2′-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-3H-imidazole-4-carboxylicacid ((R)-1-hydroxycarbamoylmethyl-2-phenylethyl)amide. MS m/z: [M+H⁺]calcd for C₃₂H₃₄N₈O₃, 579.28. found 580.0.

(6-36) 2-mercaptomethyl-4-methylpentanoic acid{2-butyl-3-[2′-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-3H-imidazol-4-ylmethyl}amide.MS m/z: [M+H⁺] calcd for C₂₉H₃₇N₇OS, 532.28. found 532.2.

(6-37)N-{2-butyl-3-[2′-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-3H-imidazol-4-ylmethyl}-N′-hydroxy-2-isobutylmalonamide.MS m/z: [M+H⁺] calcd for C₂₉H₃₆N₈O₃, 545.29. found 545.5.

(6-38) (R)-2-mercaptomethyl-4-methylpentanoic acid{2-butyl-5-chloro-3-[2′-(2H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-3H-imidazol-4-ylmethyl}amide.MS m/z: [M+H⁺] calcd for C₂₉H₃₆ClN₇OS, 566.24. found 567.

(6-39) (R)-2-mercaptomethyl-4-methylpentanoic acid{2-butyl-3-[2′-(2H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-3H-imidazol-4-ylmethyl}amide.MS m/z: [M+H⁺] calcd for C₂₉H₃₇N₇OS, 532.28. found 532.

(6-40)2-butyl-3-[2′-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-3H-imidazole-4-carboxylicacid[(R)-1-hydroxycarbamoylmethyl-2-(2-trifluoromethylphenyl)ethyl]amide. MSm/z: [M+H⁺] calcd for C₃₃H₃₃F₃N₈O₃, 647.26. found 647.4.

(6-41) (S)-2-mercaptomethyl-4-methylpentanoic acid{2-butyl-3-[2′-(2H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-3H-imidazol-4-ylmethyl}amide.MS m/z: [M+H⁺] calcd for C₂₉H₃₇N₇OS, 532.28. found 533.

(6-42) (S)-2-mercaptomethyl-4-methylpentanoic acid{2-butyl-5-chloro-3-[2′-(2H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-3H-imidazol-4-ylmethyl}amide.MS m/z: [M+H⁴] calcd for C₂₉H₃₆ClN₇OS, 566.24. found 567.

(6-43)2-butyl-3-[2′-(2H-tetrazol-5-yl)biphenyl-4-ylmethyl]-3H-imidazole-4-carboxylicacid ((R)-1-mercaptomethyl-3-methylbutyl)amide. MS m/z: [M+H⁺] calcd forC₂₈H₃₅N₇OS, 518.26. found 518.4.

(6-44) (S)-2-mercapto-4-methyl-pentanoic acid{2-butyl-5-chloro-3-[2′-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-3H-imidazol-4-ylmethyl}amide.MS m/z: [M+H⁺] calcd for C₂₈H₃₄ClN₇OS, 552.22. found 552.4.

Example 7

Following the procedures described in the examples above, andsubstituting the appropriate starting materials and reagents, compounds7-1 to 7-8, having the following formula where R is an optionalsubstituent, were also prepared:

Ex. R¹ R² —X R⁵ R⁶ R 7-1 —COOH Cl —CH₂—NHC(O)— —SH —CH(CH₃)—CH₂CH₃ — 7-2—C(O)OC(CH₃)₃ Cl —CH₂—NHC(O)— —SC(O)CH₃ —CH(CH₃)—CH₂CH₃ — 7-3—SO₂NH—C(O)NH—(CH₂)₂CH₃ H —C(O)NH— —CH₂C(O)N(OH)H benzyl — 7-4—NHSO₂—CF₃ H —C(O)NH— —CH₂C(O)N(OH)H benzyl — 7-5 —SO₂NH—C(O)CH₃ H—C(O)NH— —CH₂C(O)N(OH)H benzyl — 7-6 —SO₂NH—C(O)NH—(CH₂)₂CH₃ H —C(O)NH——CH₂C(O)N(OH)H benzyl — 7-7 —SO₂NH—C(O)CH₃ H —C(O)NH— —CH₂C(O)N(OH)Hbenzyl — 7-8 —COOH Cl —CH₂—NHC(O)— —CH₂SH —CH₂—CH(CH₃)₂ F

(7-1)4′-{2-butyl-4-chloro-5-[(2-mercapto-3-methylpentanoylamino)methyl]imidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₂₈H₃₄ClN₃O₃S, 528.20. found 528.3.

(7-2)4′{5-[(2-acetylsulfanyl-3-methyl-pentanoylamino)methyl]-2-butyl-4-chloroimidazol-1-ylmethyl}biphenyl-2-carboxylicacid t-butyl ester. MS m/z: [M+H⁺] calcd for C₃₄H₄₄ClN₃O₄S, 626.27.found 626.5.

(7-3)2-butyl-N-(4-(hydroxyamino)-4-oxo-1-phenylbutan-2-yl)-1-((2′-(N-(propylcarbamoyl)sulfamoyl)biphenyl-4-yl)methyl)-1H-imidazole-5-carboxamide.MS m/z: [M+H⁺] calcd for C₃₅H₄₂N₆O₆S, 675.29. found 675.2.

(7-4)2-butyl-3-(2′-trifluoromethanesulfonylaminobiphenyl-4-ylmethyl)-3H-imidazole-4-carboxylicacid ((R)-1-benzyl-2-hydroxycarbamoylethyl)amide. MS m/z: [M+H⁺] calcdfor C₃₂H₃₄F₃N₅O₅S, 658.22. found 658.2.

(7-5)3-(2′-acetylsulfamoylbiphenyl-4-ylmethyl)-2-butyl-3H-imidazole-4-carboxylicacid ((R)-1-benzyl-2-hydroxycarbamoylethyl)amide. MS m/z: [M+H⁺] calcdfor C₃₃H₃₇N₅O₆S, 632.25. found 632.4.

(7-6)(R)-2-butyl-N-(4-(hydroxyamino)-4-oxo-1-phenylbutan-2-yl)-1-((2′-(N-(propylcarbamoyl)sulfamoyl)biphenyl-4-yl)methyl)-1H-imidazole-5-carboxamide.MS m/z: [M+H⁺] calcd for C₃₅H₄₂N₆O₆S, 675.29. found 675.4.

(7-7)3-(2′-Acetylsulfamoylbiphenyl-4-ylmethyl)-2-butyl-3H-imidazole-4-carboxylicacid ((S)-1-benzyl-2-hydroxycarbamoylethyl)amide. MS m/z: [M+H⁺] calcdfor C₃₃H₃₇N₅O₆S, 632.25. found 632.4.

(7-8)4′-{2-butyl-4-chloro-5-[(2-mercaptomethyl-4-methylpentanoylamino)methyl]imidazol-1-ylmethyl}-3-fluorobiphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₂₉H₃₅ClFN₃O₃S, 560.21. found 561.

Example 8

Following the procedures described in the examples above, andsubstituting the appropriate starting materials and reagents, compounds8-1 to 8-77, having the following formula, were also prepared:

Ex. R² —X R⁵ R⁶ 8-1 Cl —C(O)NH—(CH₂)₄—CH(COOH)—NHC(O)— —C(O)N(OH)Hbenzyl 8-2 Cl —C(O)NH—(CH₂)₂—CH(COOH)—NHC(O)— —C(O)N(OH)H benzyl 8-3 Cl—CH₂—NHC(O)— —SH —CH(CH₃)—CH₂CH₃ 8-4 Cl —CH₂—NHC(O)— —C(O)N(OH)H—CH₂CH(CH₃)₂ 8-5 H —C(O)NH— —CH₂C(O)N(OH)H benzyl 8-6 H —C(O)NH——CH₂C(O)N(OH)H —CH₂CH(CH₃)₂ 8-7 Cl —C(O)NH— —CH₂C(O)N(OH)H benzyl 8-8 H—C(O)NH— —CH₂C(O)N(OH)H benzyl 8-9 H —C(O)NH— —CH₂C(O)N(OH)H benzyl 8-10Cl —CH₂—NHC(O)— —CH₂SH benzyl 8-11 Cl —CH₂—NHC(O)— —CH₂SH —CH₂CH(CH₃)₂8-12 Cl —CH₂—NHC(O)— —NHC(O)CH₂SH benzyl 8-13 Cl —CH₂—NHC(O)— —CH₂SH—CH(CH₃)₂ 8-14 Cl —CH₂—NHC(O)— —CH₂SH —CH₃ 8-15 Cl—CH₂—NHC(O)—CH₂—NHC(O)— —CH₂SH benzyl 8-16 Cl —CH₂—NHC(O)——CH₂C(O)N(OH)H —CH₂CH(CH₃)₂ 8-17 H —C(O)NH— —CH₂C(O)N(OH)H4-methylbenzyl 8-18 H —C(O)NH— —CH₂C(O)N(OH)H 3,4-difluorobenzyl 8-19 H—C(O)NH—CH₂— —C(O)N(OH)H benzyl 8-20 Cl —C(O)NH— —CH₂C(O)N(OH)H—CH₂-pyridin-4-yl 8-21 H —C(O)NH— —CH₂C(O)N(OH)H —CH₂-naphthalen-2-yl8-22 H —C(O)NH— —CH₂C(O)N(OH)H 4-methylbenzyl 8-23 H —C(O)NH——CH₂C(O)N(OH)H 4-chlorobenzyl 8-24 H —C(O)NH——CH₂—C(O)NH[OC(O)OCH₂-phenyl] benzyl 8-25 H —C(O)NH——CH₂—C(O)N[OC(O)CH₂O-phenyl]H benzyl 8-26 H —CH₂—NHC(O)— —CH₂SH—CH₂CH(CH₃)₂ 8-27 H —C(O)NH— —CH₂C(O)N(OH)H —(CH₂)₂-phenyl 8-28 H—C(O)NH— —CH₂C(O)N(OH)H —CH₂-thiophen-3-yl 8-29 H —C(O)NH——CH₂C(O)N(OH)H —CH₂-furan-2-yl 8-30 H —CH₂—NHC(O)— —C(O)N(OH)H—CH₂CH(CH₃)₂ 8-31 H —CH₂—NHC(O)— —C(O)N(OH)H benzyl 8-32 H —C(O)NH——CH₂—C(O)N[OC(S)N(CH₃)₂]H benzyl 8-33 H —C(O)NH— —CH₂C(O)N(OH)H4-trifluoromethylbenzyl 8-34 H —C(O)NH— —CH₂C(O)N(OH)H—CH₂-naphthalen-2-yl 8-35 H —C(O)NH— —CH₂C(O)N(OH)H 4-fluorobenzyl 8-36H —C(O)NH— —CH₂C(O)N(OH)H 3-fluorobenzyl 8-37 H —C(O)NH— —CH₂C(O)N(OH)H4-bromobenzyl 8-38 H —C(O)NH— —CH₂C(O)N(OH)H 2-bromobenzyl 8-39 H—C(O)NH— —CH₂C(O)N(OH)H 4-nitrobenzyl 8-40 H —C(O)NH— —CH₂C(O)N(OH)H2-methylbenzyl 8-41 H —C(O)NH— —CH₂C(O)N(OH)H 3-methylbenzyl 8-42 H—C(O)NH— —CH₂C(O)N(OH)H pentafluorobenzyl 8-43 H —C(O)NH— —CH₂C(O)N(OH)H2,4-dichlorobenzyl 8-44 H —C(O)NH— —CH₂C(O)N(OH)H 2,4-dichlorobenzyl8-45 H —C(O)NH— —CH₂C(O)N(OH)H 3,4-dichlorobenzyl 8-46 H —C(O)NH——CH₂C(O)N(OH)H 4-iodobenzyl 8-47 H —C(O)NH— —CH₂C(O)N(OH)H 4-iodobenzyl8-48 H —C(O)NH— —CH₂C(O)N(OH)H 2-trifluoromethylbenzyl 8-49 H —C(O)NH——CH₂C(O)N(OH)H 3-trifluoromethylbenzyl 8-50 H —C(O)NH— —CH₂C(O)N(OH)H2-cyanobenzyl 8-51 H —C(O)NH— —CH₂C(O)N(OH)H 3,4-difluorobenzyl 8-52 H—C(O)NH— —CH₂C(O)N(OH)H 2-chlorobenzyl 8-53 H —C(O)NH— —CH₂C(O)N(OH)H2-fluorobenzyl 8-54 H —C(O)NH—CH(benzyl)-CH₂—NHC(O)— —C(O)N(OH)H benzyl8-55 H —C(O)NH—CH(benzyl)-CH₂—NHC(O)— —CH₂SH benzyl 8-56 H—C(O)NH—CH(benzyl)-CH₂—NHC(O)— —CH₂SH —CH₂CH(CH₃)₂ 8-57 H—C(O)NH—CH(benzyl)-CH₂—NHC(O)— —CH₂SH —CH(CH₃)₂ 8-58 Cl —CH₂—NHC(O)——CH₂SH —CH₂CH(CH₃)₂ 8-59 H —CH₂—NHC(O)— —CH₂SH —CH₂CH(CH₃)₂ 8-60 H—C(O)NH—CH(benzyl)-CH₂—C(O)NH— —CH₂C(O)N(OH)H benzyl 8-61 H —CH₂—NHC(O)——CH₂SH —CH₂CH(CH₃)₂ 8-62 H —C(O)NH—CH(benzyl)-CH₂—C(O)NH— —CH₂SH benzyl8-63 H —C(O)NH— —CH₂SH benzyl 8-64 Cl —CH₂—NHC(O)— —CH₂SH —CH₂CH(CH₃)₂8-65 H —CH₂—NHC(O)— —SH —CH₂CH₃ 8-66 H —C(O)NH— —CH₂SH —CH₂CH(CH₃)₂ 8-67H —C(O)NH—NHC(O)— —CH₂SH —CH₂CH(CH₃)₂ 8-68 H —C(O)NH—NHC(O)— —CH₂SHbenzyl 8-69 Cl —(CH₂)₂—NHC(O)— —CH₂SH benzyl 8-70 H —CH₂—NHC(O)— —CH₂SH—(CH₂)₃CH₃ 8-71 H —CH₂—NHC(O)— —CH₂SH —(CH₂)₂CH(CH₃)₂ 8-72 H—CH₂—NHC(O)— —CH₂SH —CH(CH₃)—CH₂CH₃ 8-73 H —CH₂—NHC(O)— —CH₂SH—CH₂-cyclopentyl 8-74 H —CH₂—NHC(O)— —CH₂SH —CH₂-cyclohexyl 8-75 H—CH₂—NHC(O)— —CH₂SH —CH₂-naphthalen-3-yl 8-76 H—CH═C(—CH₂-2-thiophene)-C(O)NH— —CH₂C(O)N(OH)H benzyl 8-77 H—CH═C(—CH₂-2-thiophene)-C(O)NH— —CH₂SC(O)CH₃ benzyl

(8-1)4-{2-butyl-5-[(S)-5-carboxy-5-(2-hydroxycarbarnoyl-3-phenylpropionylamino)pentylcarbamoyl]-4-chloroimidazol-1-ylmethyl}benzoic acid. MS m/z:[M+H⁺] calcd for C₃₂H₃₈ClN₅O₈, 656.24. found 656.2.

(8-2)4-{2-butyl-5-[(S)-3-carboxy-3-(2-hydroxycarbamoyl-3-phenylpropionylamino)propylcarbamoyl]-4-chloroimidazol-1-ylmethyl}benzoic acid. MS m/z:[M+H⁺] calcd for C₃₀H₃₄ClN₅O₈, 628.21. found 629.2.

(8-3)4-{2-butyl-4-chloro-5-[(2-mercapto-3-methyl-pentanoylamino)methyl]imidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₂H₃₀ClN₃O₃S, 452.17. found 452.2.

(8-4)4-{2-butyl-4-chloro-5-[(2-hydroxycarbamoyl-4-methyl-pentanoylamino)methyl]imidazol-1-ylmethyl}benzoic acid. MS m/z: [M+H⁺] calcd forC₂₃H₃₁ClN₄O₅, 479.20. found 479.2.

(8-5)4-[5-(1-benzyl-2-hydroxycarbamoylethylcarbamoyl)-2-butylimidazol-1-ylmethyl]benzoicacid. MS m/z: [M+H⁺] calcd for C₂₆H₃₀N₄O₅, 479.22. found 479.3.

(8-6)4-[2-butyl-5-(1-hydroxycarbamoylmethyl-3-methyl-butylcarbamoyl)imidazol-1-ylmethyl]benzoicacid. MS m/z: [M+H⁺] calcd for C₂₃H₃₂N₄O₅, 445.24. found 445.2.

(8-7)4-[5-(1-benzyl-2-hydroxycarbamoylethylcarbamoyl)-2-butyl-4-chloroimidazol-1-ylmethyl]benzoicacid. MS m/z: [M+H⁺] calcd for C₂₆H₂₉ClN₄O₅, 513.18. found 513.3.

(8-8)4-[5-((R)-1-benzyl-2-hydroxycarbamoylethylcarbamoyl)-2-butylimidazol-1-ylmethyl]benzoicacid. MS m/z: [M+H⁺] calcd for C₂₆H₃₀N₄O₅, 479.22. found 479.4.

(8-9)4-[5-((S)-1-benzyl-2-hydroxycarbamoylethylcarbamoyl)-2-butylimidazol-1-ylmethyl]benzoicacid. MS m/z: [M+H⁺] calcd for C₂₆H₃₀N₄O₅, 479.22. found 479.3. For theTFA salt: ¹H-NMR (400 Mz, (CD₃)₂SO): δ (ppm) 0.74 (t, 3H, J=5 Hz), 1.20(q, 2H, J=5 Hz), 1.41 (m, 2H), 2.19 (d, 2H, J=5 Hz), 2.73 (m, 3H), 5.69(m, 4H), 7.11 (m, 7H, J=5 Hz), 7.85 (m, 2H), 8.50 (s, 1H).

(8-10)4-{2-butyl-4-chloro-5-[(2-mercaptomethyl-3-phenylpropionylamino)methyl]imidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₆H₃₀ClN₃O₃S, 500.17. found 501.

(8-11)4-{2-butyl-4-chloro-5-[(2-mercaptomethyl-4-methyl-pentanoylamino)methyl]imidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₃H₃₂ClN₃O₃S, 466.19. found 467.

(8-12)4-(2-butyl-4-chloro-5-{[2-(2-mercapto-acetylamino)-3-phenylpropionylamino]-methyl}imidazol-1-ylmethyl)benzoicacid. MS m/z: [M+H⁺] calcd for C₂₇H₃₁ClN₄O₄S, 543.18. found 544.

(8-13)4-{2-butyl-4-chloro-5-[(2-mercaptomethyl-3-methyl-butyrylamino)methyl]imidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₂H₃₀ClN₃O₃S, 452.17. found 453.

(8-14)4-{2-butyl-4-chloro-5-[((S)-3-mercapto-2-methylpropionylamino)methyl]imidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₀H₂₆ClN₃O₃S, 424.14; found 425.

(8-15)4-(5-{[2-(2-benzyl-3-mercaptopropionylamino)acetylamino]methyl}-2-butyl-4-chloroimidazol-1-ylmethyl)benzoicacid. MS m/z: [M+H⁺] calcd for C₂₈H₃₃ClN₄O₄S, 557.19. found 558.

(8-16)4-{2-butyl-4-chloro-5-[(2-hydroxycarbamoylmethyl-4-methylpentanoylamino)methyl]imidazol-1-ylmethyl}benzoic acid. MS m/z: [M+H⁺] calcd forC₂₄H₃₃ClN₄O₅, 493.21. found 494.

(8-17)4-{2-butyl-5-[(S)-2-hydroxycarbamoyl-1-(4-methylbenzyl)ethylcarbamoyl]imidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₇H₃₂N₄O₅, 493.24. found 493.4.

(8-18)4-{2-butyl-5-[(S)-1-(3,4-difluorobenzyl)-2-hydroxycarbamoylethylcarbamoyl]imidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₆H₂₈F₂N₄O₅, 515.20. found 515.2.

(8-19)4-[2-butyl-5-(2-hydroxycarbamoyl-3-phenyl-propylcarbamoyl)imidazol-1-ylmethyl]benzoicacid. MS m/z: [M+H⁺] calcd for C₂₆H₃₀N₄O₅, 479.22. found 480.2.

(8-20)4-[2-butyl-4-chloro-5-((R)-2-hydroxycarbamoyl-1-pyridin-4-ylmethylethylcarbamoyl)imidazol-1-ylmethyl]benzoicacid. MS m/z: [M+H⁺] calcd for C₂₅H₂₈ClN₅O₅, 514.18. found 515.2.

(8-21)4-[2-butyl-5-((R)-2-hydroxycarbamoyl-1-naphthalen-2-ylmethylethylcarbamoyl)imidazol-1-ylmethyl]benzoicacid. MS m/z: [M+H⁺] calcd for C₃₀H₃₂N₄O₅, 529.24. found 529.4.

(8-22)4-{2-butyl-5-[(R)-2-hydroxycarbamoyl-1-(4-methylbenzyl)ethylcarbamoyl]imidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₇H₃₂N₄O₅, 493.24. found 493.4.

(8-23)4-{2-butyl-5-[(R)-1-(4-chlorobenzyl)-2-hydroxycarbamoylethylcarbamoyl]imidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₆H₂₉ClN₄O₅, 513.18. found 514.2.

(8-24)(S)-4-((5-(4-(benzyloxycarbonyloxyamino)-4-oxo-1-phenylbutan-2-ylcarbamoyl)-2-butyl-1H-imidazol-1-yl)methyl)benzoicacid. MS m/z: [M+H⁺] calcd for C₃₄H₃₆N₄O₇, 613.26. found 613.2.

(8-25)4-(2-butyl-5-{(S)-1-[(2-phenoxyacetoxycarbamoyl)methyl]-2-phenylethylcarbamoyl}imidazol-1-ylmethyl)benzoicacid. MS m/z: [M+H⁺] calcd for C₃₄H₃₆N₄O₇, 613.26. found 613.4.

(8-26)4-[2-butyl-5-[(2-mercaptomethyl-4-methyl-pentanoylamino)methyl]imidazol-1-ylmethyl]benzoicacid. MS m/z: [M+H⁺] calcd for C₂₃H₃₃N₃O₃S, 432.22. found 433. ¹H-NMR(DMSO) 8.07 (2H, d), 7.6 (1H, s), 7.2 (2H, d), 5.6 (2H, s), 4.45 (1H,d), 4.32 (1H, d), 2.9 (2H, t), 2.55 (2H, m), 2.4 (1H, m), 1.58 (2H, m),1.35 (5H, m), 0.83 (9H, m).

(8-27)4-[2-butyl-5-((R)-1-hydroxycarbamoylmethyl-3-phenylpropylcarbamoyl)imidazol-1-ylmethyl]benzoic acid. MS m/z: [M+H⁺] calcd for C₂₇H₃₂N₄O₅,493.24. found 493.5.

(8-28)4-[2-butyl-5-((R)-2-hydroxycarbamoyl-1-thiophen-3-ylmethyl-ethylcarbamoyl)imidazol-1-ylmethyl]benzoic acid. MS m/z: [M+H⁺] calcd for C₂₄H₂₈N₄O₅S,485.18. found 485.5.

(8-29)4-[2-butyl-5-((R)-1-furan-2-ylmethyl-2-hydroxycarbamoylethylcarbamoyl)imidazol-1-ylmethyl]benzoic acid. MS m/z: [M+H⁺] calcd for C₂₄H₂₈N₄O₆,469.20. found 469.5.

(8-30)4-{2-butyl-5-[(2-hydroxycarbamoyl-4-methylpentanoylamino)methyl]imidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₃H₃₂N₄O₅, 445.24. found 445.2. ¹H-NMR(DMSO) 10.6 (1H, s), 8.92 (1H, s), 8.15 (1H, t), 7.91 (2H, d), 7.41 (1H,s), 7.15 (2H, d), 5.53 (2H, s), 4.19 (2H, d), 2.89 (1H, t), 2.81 (2H,t), 1.48 (3H, m), 1.21, 4H, m), 0.74 (9H, m).

(8-31)4-{2-butyl-5-[(2-hydroxycarbamoyl-3-phenylpropionylamino)methyl]imidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₆H₃₀N₄O₅, 479.22. found 479.0.

(8-32)(S)-4-((2-butyl-5-(4-(dimethylcarbarnothioyloxyamino)-4-oxo-1-phenylbutan-2-ylcarbamoyl)-1H-imidazol-1-yl)methyl)benzoicacid. MS m/z: [M+H⁺] calcd for C₂₉H₃₅N₅O₅S, 566.24. found 566.2.

(8-33)4-{2-butyl-5-[(R)-2-hydroxycarbamoyl-1-(4-trifluoromethylbenzyl)ethyl-carbamoyl]imidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₇H₂₉F₃N₄O₅, 547.21. found 547.7.

(8-34)4-[2-butyl-5-((R)-2-hydroxycarbamoyl-1-naphthalen-2-ylmethylethyl-carbamoyl)imidazol-1-ylmethyl]benzoicacid. MS m/z: [M+H⁺] calcd for C₃₀H₃₂N₄O₅, 529.24. found 529.7.

(8-35)4-{2-butyl-5-[(R)-1-(4-fluorobenzyl)-2-hydroxycarbamoylethylcarbamoyl]imidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₆H₂₉FN₄O₅, 497.21. found 497.6.

(8-36)4-{2-butyl-5-[(R)-1-(3-fluorobenzyl)-2-hydroxycarbamoylethylcarbamoyl]imidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₆H₂₉FN₄O₅, 497.21. found 497.7.

(8-37)4-{5-[(R)-1-(4-bromobenzyl)-2-hydroxycarbamoylethylcarbamoyl]-2-butylimidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₆H₂₉BrN₄O₅, 557.13. found 558.5.

(8-38)4-{5-[(R)-1-(2-bromobenzyl)-2-hydroxycarbamoylethylcarbamoyl]-2-butylimidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₆H₂₉BrN₄O₅, 557.13. found 558.4.

(8-39)4-{2-Butyl-5-[(R)-2-hydroxycarbamoyl-1-(4-nitrobenzyl)ethylcarbamoyl]-imidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₆H₂₉N₅O₇, 524.212. found 524.7.

(8-40)4-{2-butyl-5-[(R)-2-hydroxycarbamoyl-1-(2-methylbenzyl)ethylcarbamoyl]imidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₇H₃₂N₄O₅, 493.24. found 493.8.

(8-41)4-{2-butyl-5-[(R)-2-hydroxycarbamoyl-1-(3-methylbenzyl)ethylcarbamoyl]imidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₇H₃₂N₄O₅, 493.24. found 493.7.

(8-42)4-[2-butyl-5-((R)-2-hydroxycarbamoyl-1-pentafluorophenylmethylethyl-carbamoyl)imidazol-1-ylmethyl]benzoicacid. MS m/z: [M+H⁺] calcd for C₂₆H₂₅F₅N₄O₅, 569.17. found 569.7.

(8-43)4-{2-butyl-5-[(S)-1-(2,4-dichlorobenzyl)-2-hydroxycarbamoylethylcarbamoyl]imidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₆H₂₈Cl₂N₄O₅, 547.14. found 548.4.

(8-44)4-{2-butyl-5-[(R)-1-(2,4-dichlorobenzyl)-2-hydroxycarbamoylethylcarbamoyl]imidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₆H₂₈Cl₂N₄O₅, 547.14. found 548.5.

(8-45)4-{2-butyl-5-[(R)-1-(3,4-dichlorobenzyl)-2-hydroxycarbamoylethylcarbamoyl]imidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₆H₂₈Cl₂N₄O₅, 547.14; found 548.6.

(8-46)4-{2-butyl-5-[(S)-2-hydroxycarbamoyl-1-(4-iodobenzyl)ethylcarbamoyl]imidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₆H₂₉N₄O₅, 605.12. found 605.5.

(8-47)4-{2-butyl-5-[(R)-2-hydroxycarbamoyl-1-(4-iodobenzyl)ethylcarbamoyl]imidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₆H₂₉1N₄O₅, 605.12. found 605.5.

(8-48)4-{2-butyl-5-[(R)-2-hydroxycarbamoyl-1-(2-trifluoromethylbenzyl)ethyl-carbamoyl]imidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₇H₂₉F₃N₄O₅, 547.21. found 547.6.

(8-49)4-{2-butyl-5-[(R)-2-hydroxycarbamoyl-1-(3-trifluoromethylbenzyl)ethyl-carbamoyl]imidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₇H₂₉F₃N₄O₅, 547.21. found 547.6.

(8-50)4-{2-butyl-5-[(R)-1-(2-cyanobenzyl)-2-hydroxycarbamoylethylcarbamoyl]imidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₇H₂₉N₅O₅, 504.22. found 504.7.

(8-51)4-{2-butyl-5-[(R)-1-(3,4-difluorobenzyl)-2-hydroxycarbamoylethylcarbamoyl]imidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₆H₂₈F₂N₄O₅, 515.20; found 515.8.

(8-52)4-{2-butyl-5-[(R)-1-(2-chlorobenzyl)-2-hydroxycarbamoylethylcarbamoyl]imidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₆H₂₉ClN₄O₅, 513.18. found 514.3.

(8-53)4-{2-butyl-5-[(R)-1-(2-fluorobenzyl)-2-hydroxycarbamoylethylcarbamoyl]imidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₆H₂₉FN₄O₅, 497.21. found 497.5.

(8-54)4-(2-butyl-5-{(S)-1-[(2-hydroxycarbamoyl-3-phenylpropionylamino)methyl]-2-phenylethylcarbamoyl}imidazol-1-ylmethyl)benzoicacid. MS m/z: [M+H⁺] calcd for C₃₅H₃₉N₅O₆, 626.29. found 626.4.

(8-55)4-(2-butyl-5-{(S)-1-[(2-mercaptomethyl-3-phenylpropionylamino)methyl]-2-phenylethylcarbamoyl}imidazol-1-ylmethyl)benzoicacid. MS m/z: [M+H⁺] calcd for C₃₅H₄₀N₄O₄S, 613.28. found 613.4.

(8-56)4-(2-butyl-5-{(S)-1-[(2-mercaptomethyl-4-methylpentanoylamino)methyl]-2-phenylethylcarbamoyl}imidazol-1-ylmethyl)benzoicacid. MS m/z: [M+H⁺] calcd for C₃₂H₄₂N₄O₄S, 579.29. found 579.4.

(8-57)4-(2-butyl-5-{(S)-1-[(2-mercaptomethyl-3-methylbutyrylamino)methyl]-2-phenylethylcarbamoyl}imidazol-1-ylmethyl)benzoicacid. MS m/z: [M+H⁺] calcd for C₃₁H₄₀N₄O₄S, 565.28. found 565.2.

(8-58)4-{2-butyl-4-chloro-5-[((R)-2-mercaptomethyl-4-methylpentanoylamino)methyl]imidazol-1-ylmethyl}benzoic acid. MS m/z: [M+H⁺] calcd forC₂₃H₃₂ClN₃O₃S, 466.19. found 466.3.

(8-59)4-{2-butyl-5-[((R)-2-mercaptomethyl-4-methylpentanoylamino)methyl]imidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₃H₃₃N₃O₃S, 432.22. found 432.3. ¹H-NMR(DMSO) 8.52 (1H, t), 7.92 (2H, d), 7.48 (1H, s), 7.18 (2H, d), 5.55 (2H,s), 4.21 (2H, m), 2.84 (2H, t), 2.16 (1H, t), 1.46 (2H, m), 1.22 (5H,m), 0.76 (9H, m).

(8-60)4-{5-[(S)-1-benzyl-2-((R)-1-benzyl-2-hydroxycarbamoylethylcarbamoyl)ethylcarbamoyl]-2-butylimidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₃₆H₄₁N₅O₆, 640.31. found 640.3.

(8-61)4-{2-butyl-5-[((S)-2-mercaptomethyl-4-methyl-pentanoylamino)methyl]imidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₃H₃₃N₃O₃S, 432.22. found 432.

(8-62)4-{5-[(S)-1-benzyl-2-((R)-1-mercaptomethyl-2-phenylethylcarbamoyl)ethylcarbamoyl]-2-butylimidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₃₅H₄₀N₄O₄S, 613.28. found 613.4.

(8-63)4-[5-((R)-1-benzyl-2-mercaptoethylcarbamoyl)-2-butylimidazol-1-ylmethyl]benzoicacid. MS m/z: [M+H⁺] calcd for C₂₅H₂₉N₃O₃S, 452.19. found 452.2.

(8-64)4-{2-butyl-4-chloro-5-[((S)-2-mercaptomethyl-4-methylpentanoylamino)methyl]imidazol-1-ylmethyl}benzoic acid. MS m/z: [M+H⁺] calcd forC₂₃H₃₂ClN₃O₃S, 466.19. found 467.2.

(8-65)4-{2-butyl-5-[(2-mercaptobutyrylamino)methyl]imidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₀H₂₇N₃O₃S, 390.18. found 390.2.

(8-66)4-[2-butyl-5-((R)-1-mercaptomethyl-3-methylbutylcarbamoyl)imidazol-1-ylmethyl]benzoicacid. MS m/z: [M+H⁺] calcd for C₂₂H₃₁N₃O₃S, 418.21. found 418.2.

(8-67)4-{2-butyl-5-[N′-(2-mercaptomethyl-4-methylpentanoyl)hydrazinocarbonyl]imidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₃H₃₂N₄O₄S, 461.21. found 461.4.

(8-68)4-{5-[N′-(2-benzyl-3-mercapto-propionyl)hydrazinocarbonyl]-2-butylimidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₆H₃₀N₄O₄S, 495.20. found 495.4.

(8-69)4-{5-[2-(2-benzyl-3-mercaptopropionylamino)ethyl]-2-butyl-4-chloroimidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₇H₃₂ClN₃O₃S, 514.19. found 514.2.

(8-70)4-{2-butyl-5-[(2-mercaptomethylhexanoylamino)methyl]imidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₃H₃₃N₃O₃S, 432.22. found 432.2.

(8-71)4-{2-butyl-5-[(2-mercaptomethyl-5-methylhexanoylamino)methyl]imidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₄H₃₅N₃O₃S, 446.24. found 446.2.

(8-72)4-{2-butyl-5-[(2-mercaptomethyl-3-methyl-pentanoylamino)methyl]imidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₃H₃₃N₃O₃S, 432.22. found 432.2.

(8-73)4-{2-butyl-5-[(3-cyclopentyl-2-mercaptomethylpropionylamino)methyl]imidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₅H₃₅N₃O₃S, 458.24. found 458.2.

(8-74)4-{2-butyl-5-[(3-cyclohexyl-2-mercaptomethylpropionylamino)methyl]imidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₆H₃₇N₃O₃S, 472.26. found 472.2.

(8-75)4-{2-butyl-5-[(2-mercaptomethyl-3-naphthalen-1-ylpropionylamino)methyl]imidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₃₀H₃₃N₃O₃S, 516.22; found 517.2.

(8-76)4-{5-[(E)-2-((R)-1-benzyl-2-hydroxycarbamoylethylcarbamoyl)-3-thiophen-2-ylpropenyl]-2-butylimidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₃₃H₃₆N₄O₅S, 601.24. found 602.5.

(8-77)4-{5-[(E)-2-((R)-2-acetylsulfanyl-1-benzylethylcarbamoyl)-3-thiophen-2-ylpropenyl]-2-butylimidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₃₄H₃₇N₃O₄S₂, 616.22. found 616.4.

Example 9

Following the procedures described in the examples above, andsubstituting the appropriate starting materials and reagents, compounds9-1 to 9-63, having the following formula where one or two R groups areoptionally present, were also prepared. For Compounds 9-1 to 9-60, R³ is—(CH₂)₃CH₃. For Compounds, 9-61 to 9-63, R³ is —(CH₂)₂CH₃.

Ex. R R² —X R⁵ R⁶ 9-1 3-methoxy Cl —CH₂—NHC(O)— —CH₂SH —CH₂CH(CH₃)₂ 9-23-methoxy Cl —CH₂—NHC(O)— —CH₂SH benzyl 9-3 3-methoxy Cl —CH₂—NHC(O)——CH₂SH —CH(CH₃)₂ 9-4 3-methoxy Cl —CH₂—NHC(O)—CH₂—NHC(O)— —CH₂SH benzyl9-5 3-methoxy Cl —CH₂—NHC(O)— —C(O)N(OH)H —CH₂CH(CH₃)₂ 9-6 3-methoxy Cl—CH₂—NHC(O)— —C(O)N(OH)H benzyl 9-7 2-bromo Cl —CH₂—NHC(O)— —C(O)N(OH)H—CH₂CH(CH₃)₂ 9-8 2-bromo Cl —CH₂—NHC(O)— —C(O)N(OH)H benzyl 9-9 2-bromoCl —CH₂—NHC(O)— —CH₂SH —CH₂CH(CH₃)₂ 9-10 2-phenyl Cl —CH₂—NHC(O)— —CH₂SH—CH₂CH(CH₃)₂ 9-11 2-bromo H —CH₂—NHC(O)— —CH₂SH —CH₂CH(CH₃)₂ 9-122-bromo H —CH₂—NHC(O)— —CH₂SH —CH₂CH(CH₃)₂ 9-13 2-fluoro H —CH₂—NHC(O)——CH₂SH —CH₂CH(CH₃)₂ 9-14 2-bromo H —C(O)NH— —CH₂—C(O)N(OH)H2-bromobenzyl 9-15 2-bromo H —C(O)NH— —CH₂—C(O)N(OH)H 2-methylbenzyl9-16 3-fluoro H —CH₂—NHC(O)— —CH₂SH —CH₂CH(CH₃)₂ 9-17 2,6-difluoro H—CH₂—NHC(O)— —CH₂SH —CH₂CH(CH₃)₂ 9-18 3-fluoro H —CH₂—NHC(O)— —CH₂SH—CH₂CH(CH₃)₂ 9-19 2,6-difluoro H —CH₂—NHC(O)— —CH₂SH —CH₂CH(CH₃)₂ 9-202-bromo H —CH₂—NHC(O)— —CH₂SC(O)-phenyl-OCH₃ —CH₂CH(CH₃)₂ 9-21 2-bromo H—CH₂—NHC(O)— —CH₂SC(O)—CH₃ —CH₂CH(CH₃)₂ 9-22 2-bromo H —CH₂—NHC(O)——CH₂SC(O)—CH(CH₃)₂ —CH₂CH(CH₃)₂ 9-23 2-bromo H —CH₂—NHC(O)——CH₂SC(O)—C(CH₃)₂ —CH₂CH(CH₃)₂ 9-24 2-bromo H —CH₂—NHC(O)——CH₂SC(O)CH₂—CH(CH₃)₂ —CH₂CH(CH₃)₂ 9-25 2-bromo H —CH₂—NHC(O)——CH₂-SC(O)-cyclohexyl —CH₂CH(CH₃)₂ 9-26 2-bromo H —CH₂—NHC(O)——CH₂SC(O)-phenyl —CH₂CH(CH₃)₂ 9-27 2-bromo H —C(O)NH— —CH₂SH benzyl 9-282-bromo H —C(O)NH— —CH₂SH —CH₂CH(CH₃)₂ 9-29 2-fluoro H —CH₂—NHC(O)— —SH—CH₃ 9-30 2-fluoro H —CH₂—NHC(O)— —SH —CH₂CH₃ 9-31 2-fluoro H—CH₂—NHC(O)— —SH —(CH₂)₂CH₃ 9-32 2-fluoro H —CH₂—NHC(O)— —SH —(CH₂)₃CH₃9-33 2-fluoro H —CH₂—NHC(O)— —CH₂SH —CH₂CH(CH₃)₂ 9-34 2-methyl H—CH₂—NHC(O)— —CH₂SH —CH₂CH(CH₃)₂ 9-35 2-methoxy H —CH₂—NHC(O)— —CH₂SH—CH₂CH(CH₃)₂ 9-36 2-chloro H —CH₂—NHC(O)— —CH₂SH —CH₂CH(CH₃)₂ 9-373-bromo H —CH₂—NHC(O)— —CH₂SH —CH₂CH(CH₃)₂ 9-38 2-fluoro H —CH₂—NHC(O)——SH —CH(CH₃)—CH₂CH₃ 9-39 2-fluoro H —CH₂—NHC(O)— —SH —CH₂CH(CH₃)₂ 9-402-fluoro H —CH₂—NHC(O)— —SH —(CH₂)₄CH₃ 9-41 3-chloro H —CH₂—NHC(O)——CH₂SH —CH₂CH(CH₃)₂ 9-42 2-chloro H —CH₂—NHC(O)— —CH₂SH —CH₂CH(CH₃)₂9-43 2,5-difluoro H —CH₂—NHC(O)— —CH₂SH —CH₂CH(CH₃)₂ 9-44 2-fluoro H—CH₂—NHC(O)— —SH phenyl 9-45 2-fluoro H —CH₂—NHC(O)— —SH 4-fluorophenyl9-46 2-fluoro H —CH₂—NHC(O)— —SH —CH₂C(CH₃)₃ 9-47 2,5-difluoro H—CH₂—NHC(O)— —CH₂SH —CH₂CH(CH₃)₂ 9-48 2,3-difluoro H —CH₂—NHC(O)— —CH₂SH—CH₂CH(CH₃)₂ 9-49 2,3-difluoro H —CH₂—NHC(O)— —CH₂SH —CH₂CH(CH₃)₂ 9-502-fluoro Cl —CH₂—NHC(O)— —CH₂SH —CH₂CH(CH₃)₂ 9-51 2-fluoro Cl—CH₂—NHC(O)— —CH₂SH —CH₂CH(CH₃)₂ 9-52 2-fluoro H —CH₂—NHC(O)— —SH—CH₂CH(CH₃)₂ 9-53 2-fluoro H —CH₂—NHC(O)— —SH benzyl 9-54 2,3-difluoro H—CH₂—NHC(O)— —SH —CH₂C(CH₃)₃ 9-55 2-fluoro H —CH₂—NHC(O)— —SH—CH₂CH(CH₃)₂ 9-56 2,3-difluoro H —CH₂—NHC(O)— —SH —CH₂CH(CH₃)₂ 9-572,3-difluoro H —CH₂—NHC(O)— —CH₂SH —CH(CH₃)—CH₂CH₃ 9-58 2-fluoro H—CH₂—NHC(O)— —SH —CH₂CF₃ 9-59 2,3-difluoro H —CH₂—NHC(O)— —SH—CH₂C(CH₃)₃ 9-60 2,3-difluoro H —CH₂—NHC(O)— —SH —CH₂C(CH₃)₃ 9-612,3-difluoro —CH₂CH₃ —CH₂—NHC(O)— —CH₂SH —CH₂CH(CH₃)₂ 9-62 2,3-difluoro—CH₂CH₃ —CH₂—NHC(O)— —SH —CH₂CH(CH₃)₂ 9-63 2,3-difluoro H —CH₂—NHC(O)——SH —CH₂CH(CH₃)₂

(9-1)4-{2-butyl-4-chloro-5-[(2-mercaptomethyl-4-methylpentanoylamino)methyl]imidazol-1-ylmethyl}-3-methoxybenzoicacid. MS m/z: [M+H⁺] calcd for C₂₄H₃₄ClN₃O₄S, 496.20. found 497.2.

(9-2)4-{2-butyl-4-chloro-5-[(2-mercaptomethyl-3-phenylpropionylamino)methyl]imidazol-1-ylmethyl}-3-methoxybenzoicacid. MS m/z: [M+H⁺] calcd for C₂₇H₃₂ClN₃O₄S, 530.18. found 531.2.

(9-3)4-{2-butyl-4-chloro-5-[(2-mercaptomethyl-3-methylbutyrylamino)methyl]imidazol-1-ylmethyl}-3-methoxybenzoicacid. MS m/z: [M+H⁺] calcd for C₂₃H₃₂ClN₃O₄S, 482.18. found 483.2.

(9-4)4-(5-{[2-(2-benzyl-3-mercaptopropionylamino)-acetylamino]methyl}-2-butyl-4-chloroimidazol-1-ylmethyl)-3-methoxybenzoicacid. MS m/z: [M+H⁺] calcd for C₂₉H₃₅ClN₄O₅S, 587.20. found 588.2.

(9-5)4-{2-butyl-4-chloro-5-[(2-hydroxycarbamoyl-4-methylpentanoylamino)methyl]imidazol-1-ylmethyl}-3-methoxybenzoicacid. MS m/z: [M+H⁺] calcd for C₂₄H₃₃ClN₄O₆, 509.21. found 509.6.

(9-6)4-{2-butyl-4-chloro-5-[(2-hydroxycarbamoyl-3-phenylpropionylamino)methyl]imidazol-1-ylmethyl}-3-methoxybenzoicacid. MS m/z: [M+H⁺] calcd for C₂₇H₃₁ClN₄O₆, 543.19. found 543.6.

(9-7)2-bromo-4-{2-butyl-4-chloro-5-[(2-hydroxycarbamoyl-4-methylpentanoyl-amino)methyl]imidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₃H₃₀BrClN₄O₅, 557.11. found 558.2.

(9-8)2-bromo-4-{2-butyl-4-chloro-5-[(2-hydroxycarbamoyl-3-phenylpropionyl-amino)methyl]imidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₆H₂₈BrClN₄O₅, 591.09. found 593.2.

(9-9)2-bromo-4-{2-butyl-4-chloro-5-[(2-mercaptomethyl-4-methylpentanoylamino)methyl]imidazol-1-ylmethyl}benzoic acid. MS m/z: [M+H⁺] calcd forC₂₃H₃₁BrClN₃O₃S, 544.10. found 546.2.

(9-10)5-{2-butyl-4-chloro-5-[(2-mercaptomethyl-4-methylpentanoylamino)methyl]imidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₂₉H₃₆ClN₃O₃S, 542.22. found 543.2.

(9-11)2-bromo-4-{2-butyl-5-[((S)-2-mercaptomethyl-4-methylpentanoylamino)methyl]imidazol-1-ylmethyl}benzoic acid. MS m/z: [M+H⁺] calcd forC₂₃H₃₂BrN₃O₃S, 510.13. found 510.4. ¹H-NMR (DMSO) 8.53 (1H, t), 7.72(1H, d), 7.48 (2H, d), 7.07 (1H, d), 5.51 (2H, s), 4.23 (2H, m), 2.86(2H, t), 2.34 (1H, m), 2.17 (1H, t), 1.44, (2H, m), 1.25 (5H, m), 0.76(9H, m).

(9-12)2-bromo-4-{2-butyl-5-[((R)-2-mercaptomethyl-4-methylpentanoylamino)methyl]imidazol-1-ylmethyl}benzoic acid. MS m/z: [M+H⁺] calcd forC₂₃H₃₂BrN₃O₃S, 510.13. found 510.4. ¹H-NMR (DMSO) 8.53 (1H, t), 7.72(1H, d), 7.48 (2H, d), 7.07 (1H, d), 5.51 (2H, s), 4.23 (2H, m), 2.86(2H, t), 2.34 (1H, m), 2.17 (1H, t), 1.44, (2H, m), 1.25 (5H, m), 0.76(9H, m).

(9-13)4-{2-butyl-5-[((S)-2-mercaptomethyl-4-methylpentanoylamino)methyl]imidazol-1-ylmethyl}-2-fluorobenzoicacid. MS m/z: [M+H⁺] calcd for C₂₃H₃₂FN₃O₃S, 450.22. found 451.2. ¹H-NMR(DMSO) 8.48 (1H, t), 7.83 (1H, t), 7.38 (1H, s), 6.95 (2H, d), 5.48 (2H,s), 4.19 (2H, m), 2.75 (2H, t), 2.30 (1H, m), 2.14 (1H, t), 1.46 (2H,m), 1.23 (5H, m), 0.76 (9H, m).

(9-14)2-bromo-4-{5-[(R)-1-(2-bromobenzyl)-2-hydroxycarbamoylethylcarbamoyl](2-butylimidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₆H₂₈Br₂N₄O₅, 635.04. found 636.0.

(9-15)2-bromo-4-{2-butyl-5-[(R)-2-hydroxycarbamoyl-1-(2-methylbenzyl)ethylcarbamoyl]imidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₇H₃BrN₄O₅, 571.15. found 572.2.

(9-16)4-{2-butyl-5-[((R)-2-mercaptomethyl-4-methylpentanoylamino)methyl]imidazol-1-ylmethyl}-3-fluorobenzoicacid. MS m/z: [M+H⁺] calcd for C₂₃H₃₂FN₃O₃S, 450.22. found 451.2. ¹H-NMR(DMSO) 8.48 (1H, t), 7.73 (2H, m), 7.46 (1H, s), 5.59 (2H, s), 4.22 (2H,m), 2.85 (2H, t), 2.3 (1H, t), 2.16 (1H, t), 1.47 (2H, m), 1.22 (5H, m),0.75 (9H, m).

(9-17)4-{2-butyl-5-[((R)-2-mercaptomethyl-4-methylpentanoylamino)methyl]imidazol-1-ylmethyl}-2,6-difluorobenzoicacid. MS m/z: [M+H⁺] calcd for C₂₃H₃₁F₂N₃O₃S, 468.21. found 469.2.¹H-NMR (DMSO) 8.49 (1H, t), 7.38 (1H, s), 6.93 (2H, d), 5.46 (2H, s),4.21 (2H, m), 2.77 (2H, t), 2.31 (1H, m), 2.18 (1H, t), 1.47 (2H, m),1.23 (5H, m), 0.78 (9H, m).

(9-18)4-{2-butyl-5-[((S)-2-mercaptomethyl-4-methylpentanoylamino)methyl]imidazol-1-ylmethyl}-3-fluorobenzoicacid. MS m/z: [M+H⁺] calcd for C₂₃H₃₂FN₃O₃S, 450.22. found 451.2. ¹H-NMR(DMSO) 8.48 (1H, t), 7.73 (2H, m), 7.46 (1H, s), 5.59 (2H, s), 4.22 (2H,m), 2.85 (21-1, t), 2.3 (1H, t), 2.16 (1H, t), 1.47 (2H, m), 1.22 (5H,m), 0.75 (9H, m).

(9-19)4-{2-butyl-5-[((S)-2-mercaptomethyl-4-methylpentanoylamino)methyl]imidazol-1-ylmethyl}-2,6-difluorobenzoicacid. MS m/z: [M+H⁺] calcd for C₂₃H₃₁F₂N₃O₃S, 468.21. found 469. ¹H-NMR(DMSO) 8.49 (1H, t), 7.38 (1H, s), 6.93 (2H, d), 5.46 (2H, s), 4.21 (2H,m), 2.77 (2H, t), 2.31 (1H, m), 2.18 (1H, t), 1.47 (2H, m), 1.23 (5H,m), 0.78 (9H, m).

(9-20)2-bromo-4-(2-butyl-5-{[2-(4-methoxybenzoylsulfanylmethyl)-4-methylpentanoylamino]methyl}imidazol-1-ylmethyl)benzoicacid. MS m/z: [M+H⁺] calcd for C₃₁H₃₈BrN₃O₅S, 644.17. found 645.2.

(9-21)4-{5-[(2-acetylsulfanylmethyl-4-methylpentanoylamino)methyl]-2-butylimidazol-1-ylmethyl}-2-bromobenzoicacid. MS m/z: [M+H⁺] calcd for C₂₅H₃₄BrN₃O₄S, 552.15. found 553.2.

(9-22)2-bromo-4-{2-butyl-5-[(2-isobutyrylsulfanylmethyl-4-methylpentanoylamino)methyl]imidazol-1-ylmethyl}benzoic acid. MS m/z: [M+H⁺] calcd forC₂₇H₃₈BrN₃O₄S, 580.18. found 581.2.

(9-23)2-bromo-4-(2-butyl-5-{[2-(2,2-dimethylpropionylsulfanylmethyl)-4-methyl-pentanoylamino]methyl}imidazol-1-ylmethyl)benzoicacid. MS m/z: [M+H⁺] calcd for C₂₈H₄₀BrN₃O₄S, 594.19. found 595.2.

(9-24) 2-bromo-4-(2-butyl-5-{[4-methyl-2-(3-methylbutyrylsulfanylmethyl)pentanoylamino]methyl}imidazol-1-ylmethyl)benzoic acid. MS m/z: [M+H⁺]calcd for C₂₈H₄₀BrN₃O₄S, 594.19. found 595.2.

(9-25)2-bromo-4-{2-butyl-5-[(2-cyclohexanecarbonylsulfanylmethyl-4-methylpentanoylamino)methyl]imidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₃₀H₄₂BrN₃O₄S, 620.21. found 621.2.

(9-26)4-{5-[(2-benzoylsulfanylmethyl-4-methylpentanoylamino)methyl]-2-butylimidazol-1-ylmethyl}-2-bromobenzoicacid. MS m/z: [M+H⁺] calcd for C₃₀H₃₆BrN₃O₄S, 614.16. found 615.2.

(9-27)4-[5-((R)-1-benzyl-2-mercaptoethylcarbamoyl)-2-butylimidazol-1-ylmethyl]-2-bromobenzoicacid. MS m/z: [M+H⁺] calcd for C₂₅H₂₈BrN₃O₃S, 530.10. found 530.2.

(9-28)2-bromo-4-[2-butyl-5-((R)-1-mercaptomethyl-3-methylbutylcarbamoyl)imidazol-1-ylmethyl]benzoic acid. MS m/z: [M+H⁺] calcd forC₂₂H₃₀BrN₃O₃S, 496.12; found 496.4.

(9-29)4-{2-butyl-5-[(2-mercaptopropionylamino)methyl]imidazol-1-ylmethyl}-2-fluorobenzoicacid. MS m/z: [M+H⁺] calcd for C₁₉H₂₄FN₃O₃S, 394.15. found 394.2.

(9-30)4-{2-butyl-5-[(2-mercaptobutyrylamino)methyl]imidazol-1-ylmethyl}-2-fluorobenzoicacid. MS m/z: [M+H⁺] calcd for C₂₀H₂₆FN₃O₃S, 408.17. found 408.2.

(9-31)4-{2-butyl-5-[(2-mercaptopentanoylamino)methyl]imidazol-1-ylmethyl}-2-fluorobenzoicacid. MS m/z: [M+H⁺] calcd for C₂₁H₂₈FN₃O₃S, 422.18. found 422.2.

(9-32)4-{2-butyl-5-[(2-mercaptohexanoylamino)methyl]imidazol-1-ylmethyl}-2-fluorobenzoicacid. MS m/z: [M+H⁺] calcd for C₂₂H₃₀FN₃O₃S, 436.20. found 436.2.

(9-33)4-{2-butyl-5-[((R)-2-mercaptomethyl-4-methylpentanoylamino)methyl]imidazol-1-ylmethyl}-2-fluorobenzoicacid. MS m/z: [M+H⁺] calcd for C₂₃H₃₂FN₃O₃S, 450.22. found 450.2. ¹H-NMR(DMSO) 8.48 (1H, t), 7.83 (1H, t), 7.38 (1H, s), 6.95 (2H, d), 5.48 (2H,s), 4.19 (2H, m), 2.75 (2H, t), 2.30 (1H, m), 2.14 (1H, t), 1.46 (2H,m), 1.23 (5H, m), 0.76 (9H, m).

(9-34)4-{2-butyl-5-[((R)-2-mercaptomethyl-4-methylpentanoylamino)methyl]imidazol-1-ylmethyl}-2-methylbenzoicacid. MS m/z: [M+H⁺] calcd for C₂₄H₃₅N₃O₃S, 446.24. found 446.6.

(9-35)4-{2-butyl-5-[((R)-2-mercaptomethyl-4-methylpentanoylamino)methyl]imidazol-1-ylmethyl}-2-methoxybenzoicacid. MS m/z: [M+H⁺] calcd for C₂₄H₃₅N₃O₄S, 462.24. found 462.6.

(9-36)4-{2-butyl-5-[((R)-2-mercaptomethyl-4-methylpentanoylamino)methyl]imidazol-1-ylmethyl}-2-chlorobenzoicacid. MS m/z: [M+H⁺] calcd for C₂₃H₃₂ClN₃O₃S, 466.19. found 466.2.

(9-37)3-bromo-4-{2-butyl-5-[((R)-2-mercaptomethyl-4-methylpentanoylamino)methyl]imidazol-1-ylmethyl}benzoic acid. MS m/z: [M+H⁺] calcd forC₂₃H₃₂BrN₃O₃S, 510.13. found 510.4.

(9-38)4-{2-butyl-5-[(2-mercapto-3-methylpentanoylamino)methyl]imidazol-1-ylmethyl}-2-fluorobenzoicacid. MS m/z: [M+H⁺] calcd for C₂₂H₃₀FN₃O₃S, 436.20. found 436.2.

(9-39)4-{2-butyl-5-[(2-mercapto-4-methylpentanoylamino)methyl]imidazol-1-ylmethyl}-2-fluorobenzoicacid. MS m/z: [M+H⁺] calcd for C₂₂H₃₀FN₃O₃S, 436.20. found 436.2.

(9-40)4-{2-butyl-5-[(2-mercaptoheptanoylamino)methyl]-imidazol-1-ylmethyl}-2-fluorobenzoicacid. MS m/z: [M+H⁺] calcd for C₂₃H₃₂FN₃O₃S, 450.22. found 450.2.

(9-41)4-{2-butyl-5-[((S)-2-mercaptomethyl-4-methylpentanoylamino)methyl]imidazol-1-ylmethyl}-3-chlorobenzoicacid. MS m/z: [M+H⁺] calcd for C₂₃H₃₂ClN₃O₃S, 466.19. found 466.4.

(9-42)4-{2-butyl-5-[((S)-2-mercaptomethyl-4-methylpentanoylamino)methyl]imidazol-1-ylmethyl}-2-chlorobenzoicacid. MS m/z: [M+H⁺] calcd for C₂₃H₃₂ClN₃O₃S, 466.19. found 466.4.

(9-43)4-{2-butyl-5-[((S)-2-mercaptomethyl-4-methylpentanoylamino)methyl]imidazol-1-ylmethyl}-2,5-difluorobenzoicacid. MS m/z: [M+H⁺] calcd for C₂₃H₃₁F₂N₃O₃S, 468.21. found 468.3.¹H-NMR (DMSO) 8.50 (1H, t), 7.70 (1H, m), 7.46 (1H, s), 6.86 (1H, m),5.55 (2H, s), 4.24 (2H, m), 2.83 (2H, t), 2.30 (1H, m), 2.16 (1H, m),1.52 (2H, m), 1.23 (5H, m), 0.76 (9H, m).

(9-44)4-{2-butyl-5-[(2-mercapto-2-phenylacetylamino)methyl]imidazol-1-ylmethyl}-2-fluorobenzoicacid. MS m/z: [M+H⁺] calcd for C₂₄H₂₆FN₃O₃S, 456.17. found 456.2.

(9-45)4-(2-butyl-5-{[2-(4-fluorophenyl)-2-mercaptoacetylamino]methyl}imidazol-1-ylmethyl)-2-fluorobenzoicacid. MS m/z: [M+H⁺] calcd for C₂₄H₂₅F₂N₃O₃S, 474.16. found 474.2.

(9-46)4-{2-butyl-5-[(2-mercapto-4,4-dimethylpentanoylamino)methyl]imidazol-1-ylmethyl}-2-fluorobenzoicacid. MS m/z: [M+H⁺] calcd for C₂₃H₃₂FN₃O₃S, 450.22. found 450.2.

(9-47)4-{2-butyl-5-[((R)-2-mercaptomethyl-4-methylpentanoylamino)methyl]imidazol-1-ylmethyl}-2,5-difluorobenzoicacid. MS m/z: [M+H⁺] calcd for C₂₃H₃₁F₂N₃O₃S, 468.21. found 468.4.

(9-48)4-{2-butyl-5-[((R)-2-mercaptomethyl-4-methylpentanoylamino)methyl]imidazol-1-ylmethyl}-2,3-difluorobenzoicacid. MS m/z: [M+H⁺] calcd for C₂₃H₃₁F₂N₃O₃S, 468.21. found 468.4.

(9-49)4-{2-butyl-5-[((S)-2-mercaptomethyl-4-methylpentanoylamino)methyl]imidazol-1-ylmethyl}-2,3-difluorobenzoicacid. MS m/z: [M+H⁺] calcd for C₂₃H₃₁F₂N₃O₃S, 468.21. found 468.4.¹H-NMR (DMSO) 8.45 (1H, m), 7.62 (1H, t), 7.42 (1H, s), 6.71 (1H, t),5.59 (2H, s), 4.21 (2H, m), 2.83 (2H, t), 2.28 (1H, m), 2.16 (1H, t),2.51 (2H, m), 1.24 (5H, m), 0.75 (9H, m).

(9-50)4-{2-butyl-4-chloro-5-[((R)-2-mercaptomethyl-4-methylpentanoylamino)methyl]imidazol-1-ylmethyl}-2-fluorobenzoic acid. MS m/z: [M+H⁺] calcdfor C₂₃H₃₁ClFN₃O₃S, 484.18. found 484.4.

(9-51)4-{2-butyl-4-chloro-5-[((S)-2-mercaptomethyl-4-methylpentanoylamino)methyl]imidazol-1-ylmethyl}-2-fluorobenzoic acid. MS m/z: [M+H⁺] calcdfor C₂₃H₃₁ClFN₃O₃S, 484.18. found 484.4.

(9-52)4-{2-butyl-5-[((R)-2-mercapto-4-methylpentanoylamino)methyl]imidazol-1-ylmethyl}-2-fluorobenzoicacid. MS m/z: [M+H⁺] calcd for C₂₂H₃₀FN₃O₃S, 436.20. found 436.2. ¹H-NMR(DMSO) 8.50 (1H, t), 7.83 (1H, t), 7.42 (1H, s), 6.96 (2H, t), 5.45 (2H,s), 4.23 (2H, m), 3.18 (2H, m), 2.75 (1H, m), 1.18-1.50 (7H, m), 0.74(9H, m).

(9-53)4-{2-butyl-5-[((S)-2-mercapto-3-phenylpropionylamino)methyl]imidazol-1-ylmethyl}-2-fluorobenzoicacid. MS m/z: [M+H⁺] calcd for C₂₅H₂₈FN₃O₃S, 470.18. found 470.4.

(9-54)4-{2-butyl-5-[(2-mercapto-4,4-dimethylpentanoylamino)methyl]imidazol-1-ylmethyl}-2,3-difluorobenzoicacid. MS m/z: [M+H⁺] calcd for C₂₃H₃₁F₂N₃O₃S, 468.21. found 468.3.

(9-55)4-{2-butyl-5-[((S)-2-mercapto-4-methylpentanoylamino)methyl]-imidazol-1-ylmethyl}-2-fluorobenzoicacid. MS m/z: [M+H⁺] calcd for C₂₂H₃₀FN₃O₃S, 436.20. found 436.4.

(9-56)4-{2-butyl-5-[((R)-2-mercapto-4-methylpentanoylamino)methyl]-imidazol-1-ylmethyl}-2,3-difluorobenzoicacid. MS m/z: [M+H⁺] calcd for C₂₂H₂₉F₂N₃O₃S, 454.19. found 454.2.

(9-57)4-{2-butyl-5-[(2-mercaptomethyl-3-methylpentanoylamino)methyl]-imidazol-1-ylmethyl}-2,3-difluorobenzoicacid. MS m/z: [M+H⁺] calcd for C₂₃H₃₁F₂N₃O₃S, 468.21. found 468.2.

(9-58)4-{2-butyl-5-[(4,4,4-trifluoro-2-mercaptobutyrylamino)methyl]-imidazol-1-ylmethyl}-2-fluorobenzoicacid. MS m/z: [M+H⁺] calcd for C₂₀H₂₃F₄N₃O₃S, 462.14; found 462.4.

(9-59)4-{2-butyl-5-[((S)-2-mercapto-4,4-dimethylpentanoylamino)methyl]-imidazol-1-ylmethyl}-2,3-difluorobenzoicacid. MS m/z: [M+H⁺] calcd for C₂₃H₃₁F₂N₃O₃S, 468.21. found 468.5.

(9-60)4-{2-butyl-5-[((R)-2-mercapto-4,4-dimethylpentanoylamino)methyl]-imidazol-1-ylmethyl}-2,3-difluorobenzoicacid. MS m/z: [M+H⁺] calcd for C₂₃H₃₁F₂N₃O₃S, 468.21. found 468.5.

(9-61)4-{4-ethyl-5-[((S)-2-mercaptomethyl-4-methylpentanoylamino)methyl]-2-propylimidazol-1-ylmethyl}-2,3-difluorobenzoicacid. MS m/z: [M+H⁺] calcd for C₂₄H₃₃F₂N₃O₃S, 482.22. found 482.3.

(9-62)-{4-ethyl-5-[((S)-2-mercapto-4-methylpentanoylamino)methyl]-2-propylimidazol-1-ylmethyl}-2,3-difluorobenzoicacid. MS m/z: [M+H⁺] calcd for C₂₃H₃₁F₂N₃O₃S, 468.21. found 468.4.

(9-63)2,3-difluoro-4-{5-[((S)-2-mercapto-4-methylpentanoylamino)methyl]-2-propyl-imidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₁H₂₇F₂N₃O₃S, 440.17. found 440.2.

Example 10

Following the procedures described in the examples above, andsubstituting the appropriate starting materials and reagents, compounds10-1 to 10-5, having the following formula, were also prepared:

  Ex. R² R³ 10-1 H —(CH₂)₂CH₃ 10-2 H —(CH₂)₂CH₃ 10-3 H —CH₂CH₃ 10-4 H—CH₂CH₃ 10-5 Cl —CH₂CH₃

(10-1)2-bromo-4-{5-[((R)-2-mercaptomethyl-4-methylpentanoylamino)methyl]-2-propylimidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₂H₃₀BrN₃O₃S, 496.12. found 497.2.

(10-2)2-bromo-4-{5-[((S)-2-mercaptomethyl-4-methylpentanoylamino)methyl]-2-propylimidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₂H₃₀BrN₃O₃S, 496.12. found 497.2.

(10-3)2-bromo-4-{2-ethyl-5-[((R)-2-mercaptomethyl-4-methylpentanoylamino)methyl]imidazol-1-ylmethyl}benzoic acid. MS m/z: [M+H⁺] calcd forC₂₁H₂₈BrN₃O₃S, 482.10. found 483.2.

(10-4)2-bromo-4-{2-ethyl-5-[((S)-2-mercaptomethyl-4-methylpentanoylamino)methyl]imidazol-1-ylmethyl}benzoic acid. MS m/z: [M+H⁺] calcd forC₂₁H₂₈BrN₃O₃S, 482.10. found 483.2. ¹H-NMR (MeOH) 8.67 (1H, t), 7.83(1H, d), 7.51 (2H, d), 7.10 (1H, d), 5.57 (2H, d), 4.47 (1H, dd), 4.61(1H, dd), 2.93 (2H, q), 2.56 (2H, m), 2.38 (1H, m), 1.36 (7H, m), 0.83(6H, dd).

(10-5)2-bromo-4-{4-chloro-2-ethyl-5-[((S)-2-mercaptomethyl-4-methylpentanoylamino)methyl]-imidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₁H₂₇BrClN₃O₃S, 516.06. found 518.0.

Example 11

Following the procedures described in the examples above, andsubstituting the appropriate starting materials and reagents, compounds11-1 to 11-20, having the following formula, were also prepared:

Ex. R^(1a) R⁶ 11-1 —CH(CH₃)—O—C(O)O—CH₂CH₃ benzyl 11-2 —CH₃—(CH₂)₂-phenyl 11-3 —CH₃ —CH₂-thiophen-3-yl 11-4 —CH₃ —CH₂-furan-2-yl11-5 —CH₃ benzyl 11-6 —CH₂CH₃ benzyl 11-7 —(CH₂)₂CH₃ benzyl 11-8—CH(CH₃)—CF₃ benzyl 11-9 —(CH₂)₂—CF₂CF₃ benzyl 11-10 —CH(CH₂F)₂ benzyl11-11 —CH(CH₃)—O—C(O)O—CH(CH₃)₂ benzyl 11-12 —CH(CH₃)—O—C(O)O-cyclohexylbenzyl 11-13 cyclopentyl benzyl 11-14 —CH(CH₃)₂ benzyl 11-15—CH₂-pyridin-4-yl benzyl 11-16 benzyl benzyl 11-17 4-fluorobenzyl benzyl11-18 4-trifluoromethylbenzyl benzyl 11-19 4-trifluoromethoxybenzylbenzyl 11-20 indan-5-yl benzyl

(11-1)4-[5-(1-benzyl-2-hydroxycarbamoylethylcarbamoyl)-2-butyl-imidazol-1-ylmethyl]benzoicacid 1-ethoxycarbonyloxyethyl ester. MS m/z: [M+H⁺] calcd forC₃₁H₃₈N₄O₈, 595.27. found 595.5.

(11-2)4-[2-butyl-5-((R)-1-hydroxycarbamoylmethyl-3-phenylpropylcarbamoyl)imidazol-1-ylmethyl]benzoic acid methyl ester. MS m/z: [M+H⁺] calcd forC₂₈H₃₄N₄O₅, 507.25. found 508.1.

(11-3)4-[2-butyl-5-((R)-2-hydroxycarbamoyl-1-thiophen-3-ylmethylethylcarbamoyl)imidazol-1-ylmethyl]benzoic acid methyl ester. MS m/z: [M+H⁺] calcd forC₂₅H₃₀N₄O₅S, 499.19. found 500.1.

(11-4)4-[2-butyl-5-((R)-1-furan-2-ylmethyl-2-hydroxycarbamoylethylcarbamoyl)imidazol-1-ylmethyl]benzoic acid methyl ester. MS m/z: [M+H⁺] calcd forC₂₅H₃₀N₄O₆, 483.22. found 483.9.

(11-5)4-[5-(1-benzyl-2-hydroxycarbamoylethylcarbamoyl)-2-butylimidazol-1-ylmethyl]benzoicacid methyl ester. MS m/z: [M+H⁺] calcd for C₂₇H₃₂N₄O₅, 493.24. found493.2.

(11-6)4-[5-(1-benzyl-2-hydroxycarbamoylethylcarbamoyl)-2-butylimidazol-1-ylmethyl]benzoicacid ethyl ester. MS m/z: [M+H⁺] calcd for C₂₈H₃₄N₄O₅, 507.25. found507.2.

(11-7)4-[5-(1-benzyl-2-hydroxycarbamoylethylcarbamoyl)-2-butylimidazol-1-ylmethyl]benzoicacid propyl ester. MS m/z: [M+H⁺] calcd for C₂₉H₃₆N₄O₅, 521.27. found521.2.

(11-8)4-[5-(1-benzyl-2-hydroxycarbamoylethylcarbamoyl)-2-butylimidazol-1-ylmethyl]benzoicacid 2,2,2-trifluoro-1-methylethyl ester. MS m/z: [M+H⁺] calcd forC₂₉H₃₃F₃N₄O₅, 575.24. found 575.

(11-9)4-[5-(1-benzyl-2-hydroxycarbamoylethylcarbamoyl)-2-butylimidazol-1-ylmethyl]benzoicacid 3,3,4,4,4-pentafluorobutyl ester. MS m/z: [M+H⁺] calcd forC₃₀H₃₃F₅N₄O₅, 625.24. found 625.

(11-10)4-[5-(1-benzyl-2-hydroxycarbamoylethylcarbamoyl)-2-butylimidazol-1-ylmethyl]benzoicacid 2-fluoro-1-fluoromethylethyl ester. MS m/z: [M+H⁺] calcd forC₂₉H₃₄F₂N₄O₅, 557.25. found 557.

(11-11)4-[5-(1-benzyl-2-hydroxycarbamoylethylcarbamoyl)-2-butylimidazol-1-ylmethyl]benzoicacid 1-isopropoxycarbonyloxyethyl ester. MS m/z: [M+H⁺] calcd forC₃₂H₄₀N4O₈, 609.28. found 609.4.

(11-12)4-[5-(1-benzyl-2-hydroxycarbamoylethylcarbamoyl)-2-butylimidazol-1-ylmethyl]benzoicacid 1-cyclohexyloxycarbonyloxyethyl ester. MS m/z: [M+H⁺] calcd forC₃₅H₄₄N₄O₈, 649.32. found 649.4.

(11-13)4-[2-butyl-5-(1-hydroxycarbamoylmethyl-2-phenylethylcarbamoyl)imidazol-1-ylmethyl]benzoicacid cyclopentyl ester. MS m/z: [M+H⁺] calcd for C₃₁H₃₈N₄O₅, 547.28.found 547.

(11-14)4-[2-butyl-5-(1-hydroxycarbamoylmethyl-2-phenylethylcarbamoyl)imidazol-1-ylmethyl]benzoicacid isopropyl ester. MS m/z: [M+H⁺] calcd for C₂₉H₃₆N₄O₅, 521.27. found521.

(11-15)4-[5-(1-benzyl-2-hydroxycarbamoylethylcarbamoyl)-2-butylimidazol-1-ylmethyl]benzoicacid pyridin-4-ylmethyl ester. MS m/z: [M+H⁺] calcd for C₃₂H₃₅N₅O₅,570.26. found 570.6.

(11-16)4-[5-(1-benzyl-2-hydroxycarbamoylethylcarbamoyl)-2-butylimidazol-1-ylmethyl]benzoicacid benzyl ester. MS m/z: [M+H⁺] calcd for C₃₃H₃₆N₄O₅, 569.27. found569.4.

(11-17)4-[5-(1-benzyl-2-hydroxycarbamoylethylcarbamoyl)-2-butylimidazol-1-ylmethyl]benzoicacid 4-fluorobenzyl ester. MS m/z: [M+H⁺] calcd for C₃₃H₃₅FN₄O₅, 587.26.found 587.0.

(11-18)4-[5-(1-benzyl-2-hydroxycarbamoylethylcarbamoyl)-2-butylimidazol-1-ylmethyl]benzoicacid 4-trifluoromethylbenzyl ester. MS m/z: [M+H⁺] calcd forC₃₄H₃₅F₃N₄O₅, 637.26. found 638.0.

(11-19)4-[5-(1-benzyl-2-hydroxycarbamoylethylcarbamoyl)-2-butylimidazol-1-ylmethyl]benzoicacid 4-trifluoromethoxybenzyl ester. MS m/z: [M+H⁺] calcd forC₃₄H₃₅F₃N₄O₆, 653.25. found 653.2.

(11-20)4-[2-butyl-5-(1-hydroxycarbamoylmethyl-2-phenylethylcarbamoyl)imidazol-1-ylmethyl]benzoicacid indan-5-yl ester. MS m/z: [M+H⁺] calcd for C₃₅H₃₈N₄O₅, 595.28.found 595.2.

Example 12

Following the procedures described in the examples above, andsubstituting the appropriate starting materials and reagents, compounds12-1 to 12-20, having the following formula where R is an optionalsubstituent, were also prepared:

Ex. R^(1a) R R⁵ R⁶ 12-1 —CH₃ — —CH₂SH —CH₂CH(CH₃)₂ 12-2 H 2-bromo —CH₂SH—CH₂CH(CH₃)₂ 12-3 —CH₃ 2-bromo —CH₂SH —CH₂CH(CH₃)₂ 12-4 —CH₃ 2-bromo—CH₂SC(O)CH₃ —CH₂CH(CH₃)₂ 12-5 —CH₂CH₃ 2-bromo —CH₂SH —CH₂CH(CH₃)₂ 12-6—CH(CH₃)₂ 2-bromo —CH₂SH —CH₂CH(CH₃)₂ 12-7 —(CH₂)₃CH₃ 2-bromo —CH₂SH—CH₂CH(CH₃)₂ 12-8 —CH₃ 2-fluoro —CH₂SC(O)CH₃ —CH₂CH(CH₃)₂ 12-9 —CH₃2-methyl —CH₂SC(O)CH₃ —CH₂CH(CH₃)₂ 12-10 —CH₃ 2-methoxy —CH₂SC(O)CH₃—CH₂CH(CH₃)₂ 12-11 —CH₃ 2-chloro —CH₂SC(O)CH₃ —CH₂CH(CH₃)₂ 12-12 —CH₃3-chloro —CH₂SC(O)CH₃ —CH₂CH(CH₃)₂ 12-13 —CH₃ 2-chloro —CH₂SC(O)CH₃—CH₂CH(CH₃)₂ 12-14 —CH₃ 2-fluoro —SC(O)CH₃ phenyl 12-15 —CH₃ 2-fluoro—SC(O)CH₃ 2-chlorophenyl 12-16 —CH₃ 2-fluoro —SC(O)CH₃ 4-fluorophenyl12-17 —CH₃ 2-fluoro —SC(O)CH₃ 4-chlorophenyl 12-18 —CH₃ 2-fluoro—SC(O)CH₃ —CH₂CH(CH₃)₂ 12-19 —CH₃ 2-fluoro —SC(O)CH₃ —CH(CH₃)₂ 12-20—CH₃ 2-fluoro —SC(O)CH₃ —CH₂C(CH₃)₃

(12-1)4-{2-butyl-5-[(2-mercaptomethyl-4-methylpentanoylamino)methyl]imidazol-1-ylmethyl}benzoicacid methyl ester. MS m/z: [M+H⁺] calcd for C₂₄H₃₅N₃O₃S, 446.24. found446.3.

(12-2)2-bromo-4-{2-butyl-5-[(2-mercaptomethyl-4-methylpentanoylamino)methyl]imidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₃H₃₂BrN₃O₃S, 510.13. found 511.

(12-3)2-bromo-4-{2-butyl-5-[(2-mercaptomethyl-4-methylpentanoylamino)methyl]imidazol-1-ylmethyl}benzoicacid methyl ester. MS m/z: [M+H⁺] calcd for C₂₄H₃₄BrN₃O₃S, 524.15. found524.4.

(12-4)4-{5-[(2-acetylsulfanylmethyl-4-methylpentanoylamino)methyl]-2-butylimidazol-1-ylmethyl}-2-bromobenzoicacid methyl ester. MS m/z: [M+H⁺] calcd for C₂₆H₃₆BrN₃O₄S, 566.16. found566.1.

(12-5)2-bromo-4-{2-butyl-5-[(2-mercaptomethyl-4-methylpentanoylamino)methyl]imidazol-1-ylmethyl}benzoicacid ethyl ester. MS m/z: [M+H⁺] calcd for C₂₅H₃₆BrN₃O₃S, 538.17. found539.2.

(12-6)2-bromo-4-{2-butyl-5-[(2-mercaptomethyl-4-methylpentanoylamino)methyl]imidazol-1-ylmethyl}benzoicacid isopropyl ester. MS m/z: [M+H⁺] calcd for C₂₆H₃₈BrN₃O₃S, 552.18.found 553.2.

(12-7)2-bromo-4-{2-butyl-5-[(2-mercaptomethyl-4-methylpentanoylamino)methyl]imidazol-1-ylmethyl}benzoicacid butyl ester. MS m/z: [M+H⁺] calcd for C₂₇H₄₀BrN₃O₃S, 566.20. found567.2.

(12-8)4-{5-[((R)-2-acetylsulfanylmethyl-4-methylpentanoylamino)methyl]-2-butyl-imidazol-1-ylmethyl}-2-fluorobenzoicacid methyl ester. MS m/z: [M+H⁺] calcd for C₂₆H₃₆FN₃O₄S, 506.24. found506.2.

(12-9)4-{5-[((R)-2-acetylsulfanylmethyl-4-methylpentanoylamino)methyl]-2-butylimidazol-1-ylmethyl}-2-methylbenzoicacid methyl ester. MS m/z: [M+H⁺] calcd for C₂₇H₃₉N₃O₄S, 502.27. found502.2.

(12-10)4-{5-[((R)-2-acetylsulfanylmethyl-4-methylpentanoylamino)methyl]-2-butylimidazol-1-ylmethyl}-2-methoxybenzoicacid methyl ester. MS m/z: [M+H⁺] calcd for C₂₇H₃₉N₃O₅S, 518.26. found518.2.

(12-11)4-{5-[((R)-2-acetylsulfanylmethyl-4-methylpentanoylamino)methyl]-2-butylimidazol-1-ylmethyl}-2-chlorobenzoicacid methyl ester. MS m/z: [M+H⁺] calcd for C₂₆H₃₆ClN₃O₄S, 522.21. found522.1.

(12-12)4-{5-[((S)-2-acetylsulfanylmethyl-4-methylpentanoylamino)methyl]-2-butylimidazol-1-ylmethyl}-3-chlorobenzoicacid methyl ester. MS m/z: [M+H⁺] calcd for C₂₆H₃₆ClN₃O₄S, 522.21. found523.2.

(12-13)4-{5-[((S)-2-acetylsulfanylmethyl-4-methylpentanoylamino)methyl]-2-butylimidazol-1-ylmethyl}-2-chlorobenzoicacid methyl ester. MS m/z: [M+H⁺] calcd for C₂₆H₃₆ClN₃O₄S, 522.21. found523.2.

(12-14)4-{5-[(2-acetylsulfanyl-2-phenylacetylamino)methyl]-2-butylimidazol-1-ylmethyl}-2-fluorobenzoicacid methyl ester. MS m/z: [M+H⁺] calcd for C₂₇H₃₀FN₃O₄S, 512.19. found512.2.

(12-15)4-(5-{[2-acetylsulfanyl-2-(2-chlorophenyl)-acetylamino]methyl}-2-butylimidazol-1-ylmethyl)-2-fluorobenzoicacid methyl ester. MS m/z: [M+H⁺] calcd for C₂₇H₂₉ClFN₃O₄S, 546.16.found 546.2.

(12-16)4-(5-{[2-acetylsulfanyl-2-(4-fluorophenyl)-acetylamino]methyl}-2-butylimidazol-1-ylmethyl)-2-fluorobenzoicacid methyl ester. MS m/z: [M+H⁺] calcd for C₂₇H₂₉F₂N₃O₄S, 530.18. found530.2.

(12-17)4-(5-{[2-acetylsulfanyl-2-(4-chlorophenyl)-acetylamino]methyl}-2-butylimidazol-1-ylmethyl)-2-fluorobenzoicacid methyl ester. MS m/z: [M+H⁺] calcd for C₂₇H₂₉ClFN₃O₄S, 546.16.found 546.2.

(12-18)4-{5-[(2-acetylsulfanyl-4-methylpentanoylamino)methyl]-2-butylimidazol-1-ylmethyl}-2-fluorobenzoicacid methyl ester. MS m/z: [M+H⁺] calcd for C₂₅H₃₄FN₃O₄S, 492.23. found492.2.

(12-19)4-{5-[(2-acetylsulfanyl-3-methylbutyrylamino)methyl]-2-butylimidazol-1-ylmethyl}-2-fluorobenzoicacid methyl ester. MS m/z: [M+H⁺] calcd for C₂₄H₃₂FN₃O₄S, 478.21. found478.2.

(12-20)4-{5-[(2-acetylsulfanyl-4,4-dimethylpentanoylamino)methyl]-2-butylimidazol-1-ylmethyl}-2-fluorobenzoicacid methyl ester. MS m/z: [M+H⁺] calcd for C₂₆H₃₆FN₃O₄S, 506.24. found506.2.

Example 13

Following the procedures described in the examples above, andsubstituting the appropriate starting materials and reagents, thefollowing compound was also prepared:

4-{5-[(R)-2-((S)-2-Acetylsulfanyl-1-benzylethylcarbamoyl)-1-benzylethyl-carbamoyl]-2-butylimidazol-1-ylmethyl}benzoicacid methyl ester. MS m/z: [M+H⁺] calcd for C₃₈H₄₄N₄O₅S, 669.30. found669.5.

Example 14

Following the procedures described in the examples above, andsubstituting the appropriate starting materials and reagents, compounds14-1 to 14-24, having the following formula, were also prepared:

Ex. R¹ R² X R⁵ R⁶ 14-1 —O—CH(CH₃)—COOH Cl —C(O)NH— —CH₂C(O)N(OH)H—CH₂CH(CH₃)₂ 14-2 —NHSO₂—CF₃ Cl —C(O)NH— —CH₂C(O)N(OH)H benzyl 14-3—NHSO₂—CF₃ H —C(O)NH— —CH₂C(O)N(OH)H benzyl 14-4 —SO₂—NHC(O)CH₃ H—C(O)NH— —CH₂C(O)N(OH)H benzyl 14-5 —SO₂—NH—C(O)NH—(CH₂)₂—CH₃ H —C(O)NH——CH₂C(O)N(OH)H benzyl 14-6 —SO₂—NH—C(O)NH—(CH₂)₂—CH₃ H —C(O)NH——CH₂C(O)N(OH)H 4-chlorobenzyl 14-7 —NHSO₂—CF₃ H —C(O)NH— —CH₂C(O)N(OH)H—CH₂CH(CH₃)₂ 14-8 —NHSO₂—CF₃ H —C(O)NH— —CH₂C(O)N(OH)H benzyl 14-9—O—CH(CH₃)—COOH Cl —C(O)NH— —CH₂C(O)N(OH)H benzyl 14-10 —O—CH(CH₃)—COOHH —C(O)NH— —CH₂C(O)N(OH)H —CH₂CH(CH₃)₂ 14-11 —C(O)O—(CH₂)₂—CF₃ H—C(O)NH— —CH₂C(O)N(OH)H benzyl 14-12 —SO₂OH H —C(O)NH— —CH₂C(O)N(OH)Hbenzyl 14-13 —SO₂OH H —C(O)NH— —CH₂C(O)N(OH)H benzyl 14-14 —SO₂OH H—C(O)NH— —CH₂C(O)N(OH)H —CH₂CH(CH₃)₂ 14-15 —SO₂OH H —C(O)NH——CH₂C(O)N(OH)H 4-chlorobenzyl 14-16 —SO₂OH H —C(O)NH— —CH₂C(O)N(OH)Hbenzyl 14-17 —NHSO₂—CF₃ H —C(O)NH— —CH₂C(O)N(OH)H benzyl 14-18tetrazolyl H —C(O)NH— —CH₂C(O)N(OH)H 2-bromobenzyl 14-19 tetrazolyl H—C(O)NH— —CH₂C(O)N(OH)H benzyl 14-20 tetrazolyl H —C(O)NH— —CH₂COOHbenzyl 14-21 tetrazolyl H —C(O)NH— —CH₂C(O)N(OH)H —CH₂CH(CH₃)₂ 14-22tetrazolyl H —C(O)NH— —CH₂SH benzyl 14-23 tetrazolyl H —C(O)NH— —CH₂SH—CH₂CH(CH₃)₂ 14-24 —SO₂NHC(O)—phenyl H —CH₂—NHC(O)— —CH₂SH —CH₂CH(CH₃)₂

(14-1)2-{4-[2-butyl-4-chloro-5-(1-hydroxycarbamoylmethyl-3-methylbutyl-carbamoyl)imidazol-1-ylmethyl]phenoxy}propionicacid. MS m/z: [M+H⁺] calcd for C₂₅H₃₅ClN₄O₆, 523.22. found 523.4.

(14-2)2-butyl-5-chloro-3-(4-trifluoromethanesulfonylaminobenzyl)-3H-imidazole-4-carboxylicacid (1-hydroxycarbamoylmethyl-2-phenylethyl)amide. MS m/z: [M+H⁺] calcdfor C₂₆H₂₉ClF₃N₅O₅S, 616.15. found 616.4.

(14-3)2-butyl-3-(4-trifluoromethanesulfonylaminobenzyl)-3H-imidazole-4-carboxylicacid (1-hydroxycarbamoylmethyl-2-phenylethyl)amide. MS m/z: [M+H⁺] calcdfor C₂₆H₃₀F₃N₅O₅S, 582.19. found 582.4.

(14-4) 3-(4-acetylsulfamoylbenzyl)-2-butyl-3H-imidazole-4-carboxylicacid (1-hydroxycarbamoylmethyl-2-phenylethyl)amide. MS m/z: [M+H⁺] calcdfor C₂₇H₃₃N₅O₆S, 556.22. found 556.3.

(14-5)2-butyl-N-(4-(hydroxyamino)-4-oxo-1-phenylbutan-2-yl)-1-(4-(N-(propylcarbamoyl)sulfamoyl)benzyl)-1H-imidazole-5-carboxamide.MS m/z: [M+H⁺] calcd for C₂₉H₃₈N₆O₆S, 599.26. found 599.4.

(14-6)(S)-2-butyl-N-(1-(4-chlorophenyl)-4-(hydroxyamino)-4-oxobutan-2-yl)-1-(4-(N-(propylcarbamoyl)sulfamoyl)benzyl)-1H-imidazole-5-carboxamide.MS m/z: [M+H⁺] calcd for C₂₉H₃₇ClN₆O₆S, 633.22. found 634.2.

(14-7)2-butyl-3-(4-trifluoromethanesulfonylaminobenzyl)-3H-imidazole-4-carboxylicacid ((S)-1-hydroxycarbamoylmethyl-3-methylbutyl)amide. MS m/z: [M+H⁺]calcd for C₂₃H₃₂F₃N₅O₅S, 548.21. found 548.3.

(14-8)2-butyl-3-(4-trifluoromethanesulfonylamino-benzyl)-3H-imidazole-4-carboxylicacid ((S)-1-benzyl-2-hydroxycarbamoylethyl)amide. MS m/z: [M+H⁺] calcdfor C₂₆H₃₀F₃N₅O₅S, 582.19. found 582.3.

(14-9)2-{4-[2-butyl-4-chloro-5-(1-hydroxycarbamoylmethyl-2-phenylethyl-carbamoyl)imidazol-1-ylmethyl]phenoxy}propionicacid. MS m/z: [M+H⁺] calcd for C₂₈H₃₃ClN₄O₆, 557.21. found 557.0.

(14-10)2-{4-[2-butyl-5-((S)-1-hydroxycarbamoylmethyl-3-methylbutylcarbamoyl)imidazol-1-ylmethyl]phenoxy}propionic acid. MS m/z: [M+H⁺] calcd forC₂₅H₃₆N₄O₆, 489.26. found 489.4.

(14-11)4-[5-(1-benzyl-2-hydroxycarbarnoylethylcarbamoyl)-2-butylimidazol-1-ylmethyl]benzoicacid 3,3,3-trifluoropropyl ester. MS m/z: [M+H⁺] calcd for C₂₉H₃₃F₃N₄O₅,575.24. found 575.4.

(14-12)4-[5-(1-benzyl-2-hydroxycarbamoylethylcarbamoyl)-2-butylimidazol-1-ylmethyl]benzenesulfonicacid. MS m/z: [M+H⁺] calcd for C₂₅H₃₀N₄O₆S, 515.19. found 515.5

(14-13)4-[5-((S)-1-benzyl-2-hydroxycarbamoylethylcarbamoyl)-2-butylimidazol-1-ylmethyl]benzenesulfonicacid. MS m/z: [M+H⁺] calcd for C₂₅H₃₀N₄O₆S, 515.19. found 515.5.

(14-14)4-[2-butyl-5-(1-hydroxycarbamoylmethyl-3-methylbutylcarbamoyl)imidazol-1-ylmethyl]benzenesulfonicacid. MS m/z: [M+H⁺] calcd for C₂₂H₃₂N₄O₆S, 481.20. found 481.2.

(14-15)4-{2-butyl-5-[(S)-1-(4-chlorobenzyl)-2-hydroxycarbamoylethylcarbamoyl]imidazol-1-ylmethyl}benzenesulfonicacid. MS m/z: [M+H⁺] calcd for C₂₅H₂₉ClN₄O₆S, 549.15. found 550.2.

(14-16)4-[5-((R)-1-benzyl-2-hydroxycarbamoyl-ethylcarbamoyl)-2-butylimidazol-1-ylmethyl]benzenesulfonicacid. MS m/z: [M+H⁺] calcd for C₂₅H₃₀N₄O₆S, 515.19. found 515.2.

(14-17)2-butyl-3-(4-trifluoromethanesulfonylaminobenzyl)-3H-imidazole-4-carboxylicacid ((R)-1-benzyl-2-hydroxycarbamoylethyl)amide. MS m/z: [M+H⁺] calcdfor C₂₆H₃₀F₃N₅O₅S, 582.19. found 582.2.

(14-18) 2-butyl-3-[4-(1H-tetrazol-5-yl)benzyl]-3H-imidazole-4-carboxylicacid [(R)-2-(2-bromophenyl)-1-hydroxycarbamoylmethylethyl]amide. MS m/z:[M+H⁺] calcd for C₂₆H₂₉BrN₈O₃, 581.15. found 583.3.

(14-19) 2-butyl-3-[4-(1H-tetrazol-5-yl)benzyl]-3H-imidazole-4-carboxylicacid ((R)-1-hydroxycarbamoylmethyl-2-phenylethyl)amide. MS m/z: [M+H⁺]calcd for C₂₆H₃₀N₈O₃, 503.24. found 503.5.

(14-20)(R)-3-({2-butyl-3-[4-(1H-tetrazol-5-yl)benzyl]-3H-imidazole-4-carbonyl}amino)-4-phenylbutyricacid. MS m/z: [M+H⁺] calcd for C₂₆H₂₉N₇O₃, 488.23. found 488.3.

(14-21) 2-butyl-3-[4-(1H-tetrazol-5-yl)benzyl]-3H-imidazole-4-carboxylicacid ((R)-1-hydroxycarbamoylmethyl-3-methylbutyl)amide. MS m/z: [M+H⁺]calcd for C₂₃H₃₂N₈O₃, 469.26. found 469.2.

(14-22) 2-butyl-3-[4-(2H-tetrazol-5-yl)benzyl]-3H-imidazole-4-carboxylicacid ((R)-1-mercaptomethyl-2-phenylethyl)amide. MS m/z: [M+H⁺] calcd forC₂₅H₂₉N₇OS, 476.22. found 476.4.

(14-23) 2-butyl-3-[4-(2H-tetrazol-5-yl)benzyl]-3H-imidazole-4-carboxylicacid ((R)-1-mercaptomethyl-3-methylbutyl)amide. MS m/z: [M+H⁺] calcd forC₂₂H₃₁N₇OS, 442.23. found 442.4.

(14-24) 2-mercaptomethyl-4-methylpentanoic acid[3-(4-benzoylsulfamoylbenzyl)-2-butyl-3H-imidazol-4-ylmethyl]amide. MSm/z: [M+H⁺] calcd for C₂₉H₃₈N₄O₄S₂, 571.23. found 571.2.

Example 15

Following the procedures described in the examples above, andsubstituting the appropriate starting materials and reagents, compounds15-1 to 15-12, having the following formula, were also prepared:

Ex. R² X R⁵ R⁶ 15-1 H —C(O)NH— —CH₂C(O)N(OH)H —CH₂CH(CH₃)₂ 15-2 Cl—CH₂—NHC(O)— —CH₂SH —CH₂CH(CH₃)₂ 15-3 Cl —CH₂—NHC(O)— —CH₂SH benzyl 15-4Cl —CH₂—NHC(O)— —CH₂SH —CH(CH₃)₂ 15-5 Cl —CH₂—NHC(O)— —SH—CH(CH₃)—CH₂CH₃ 15-6 Cl —CH₂—NHC(O)—CH₂—NHC(O)— —CH₂SH benzyl 15-7 Cl—CH₂—NHC(O)— —C(O)N(OH)H —CH₂CH(CH₃)₂ 15-8 Cl —CH₂—NHC(O)— —C(O)N(OH)Hbenzyl 15-9 H —C(O)NH— —CH₂C(O)N(OH)H benzyl 15-10 H —C(O)NH——CH₂C(O)N(OH)H benzyl 15-11 Cl —C(O)NH— —CH₂C(O)N(OH)H benzyl 15-12 Cl—C(O)NH— —CH₂C(O)N(OH)H benzyl

(15-1)3-[2-butyl-5-(1-hydroxycarbamoylmethyl-3-methylbutylcarbamoyl)imidazol-1-ylmethyl]benzoicacid. MS m/z: [M+H⁺] calcd for C₂₃H₃₂N₄O₅, 445.24. found 445.2.

(15-2)3-{2-butyl-4-chloro-5-[(2-mercaptomethyl-4-methylpentanoylamino)methyl]imidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₃H₃₂ClN₃O₃S, 466.19. found 466.2.

(15-3)3-{2-butyl-4-chloro-5-[(2-mercaptomethyl-3-phenylpropionylamino)methyl]imidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₆H₃₀ClN₃O₃S, 500.17; found 500.2.

(15-4)3-{2-butyl-4-chloro-5-[(2-mercaptomethyl-3-methylbutyrylamino)methyl]imidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₂H₃₀ClN₃O₃S, 452.17. found 452.2.

(15-5)3-{2-butyl-4-chloro-5-[(2-mercapto-3-methylpentanoylamino)methyl]imidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₂H₃₀ClN₃O₃S, 452.17. found 452.2.

(15-6)3-(5-{[2-(2-benzyl-3-mercaptopropionylamino)acetylamino]methyl}-2-butyl-4-chloroimidazol-1-ylmethyl)benzoicacid. MS m/z: [M+H⁺] calcd for C₂₈H₃₃ClN₄O₄S, 557.19. found 557.2.

(15-7)3-{2-butyl-4-chloro-5-[(2-hydroxycarbamoyl-4-methylpentanoylamino)methyl]imidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₃H₃₁ClN₄O₅, 479.20. found 479.2.

(15-8)3-{2-butyl-4-chloro-5-[(2-hydroxycarbamoyl-3-phenylpropionylamino)methyl]imidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₆H₂₉ClN₄O₅, 513.18. found 513.2.

(15-9)3-[2-butyl-5-(1-hydroxycarbamoylmethyl-2-phenylethylcarbamoyl)imidazol-1-ylmethyl]benzoicacid. MS m/z: [M+H⁺] calcd for C₂₆H₃₀N₄O₅, 479.22. found 479.4.

(15-10)3-[2-butyl-5-((R)-1-hydroxycarbamoylmethyl-2-phenylethylcarbamoyl)imidazol-1-ylmethyl]benzoic acid. MS m/z: [M+H⁺] calcd for C₂₆H₃₀N₄O₅,479.22. found 479.4.

(15-11)3-[2-butyl-4-chloro-5-((R)-1-hydroxycarbamoylmethyl-2-phenylethyl-carbamoyl)imidazol-1-ylmethyl]benzoicacid. MS m/z: [M+H⁺] calcd for C₂₆H₂₉ClN₄O₅, 513.18. found 514.2.

(15-12)3-[2-butyl-4-chloro-5-(1-hydroxycarbamoylmethyl-2-phenylethylcarbamoyl)imidazol-1-ylmethyl]benzoic acid. MS m/z: [M+H⁺] calcd for C₂₆H₂₉ClN₄O₅,513.18; found 514.2.

Example 16

Following the procedures described in the examples above, andsubstituting the appropriate starting materials and reagents, compounds16-1 to 16-4, having the following formula, were also prepared:

Ex. —X R⁶ 16-1 —CH₂—NHC(O)— —CH₂CH(CH₃)₂ 16-2 —CH₂—NHC(O)— benzyl 16-3—CH₂—NHC(O)— —CH(CH₃)₂ 16-4 —CH₂—NHC(O)—CH₂—NHC(O)— benzyl

(16-1)2-{2-butyl-4-chloro-5-[(2-mercaptomethyl-4-methylpentanoylamino)methyl]imidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₃H₃₂ClN₃O₃S, 466.19. found 467.

(16-2)2-{2-butyl-4-chloro-5-[(2-mercaptomethyl-3-phenylpropionylamino)methyl]imidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₆H₃₀ClN₃O₃S, 500.17. found 501.

(16-3)2-{2-butyl-4-chloro-5-[(2-mercaptomethyl-3-methylbutyrylamino)methyl]imidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₂H₃₀ClN₃O₃S, 452.17. found 453.

(16-4)2-(5-{[2-(2-benzyl-3-mercaptopropionylamino)acetylamino]methyl}-2-butyl-4-chloroimidazol-1-ylmethyl)benzoicacid. MS m/z: [M+H⁺] calcd for C₂₈H₃₃ClN₄O₄S, 557.19. found 558.

Example 17

Following the procedures described in the examples above, andsubstituting the appropriate starting materials and reagents, compounds17-1 to 17-14, having the following formula, were also prepared:

Ex. R² —X R⁵ R⁶ 17-1 Cl —CH₂—NHC(O)— —CH₂SH —CH₂CH(CH₃)₂ 17-2 Cl—CH₂—NHC(O)— —CH₂SH benzyl 17-3 Cl —CH₂—NHC(O)— —CH₂SH —CH(CH₃)₂ 17-4 Cl—CH₂—NHC(O)—CH₂—NHC(O)— —CH₂SH benzyl 17-5 Cl —CH₂—NHC(O)— —C(O)N(OH)H)—CH₂CH(CH₃)₂ 17-6 Cl —CH₂—NHC(O)— —C(O)N(OH)H) —CH(CH₃)₂ 17-7 H —C(O)NH——CH₂C(O)N(OH)H) —CH₂CH(CH₃)₂ 17-8 Cl —C(O)NH— —C(O)N(OH)H) benzyl 17-9 H—C(O)NH— —CH₂C(O)N(OH)H) benzyl 17-10 Cl —C(O)NH— —CH₂C(O)N(OH)H) benzyl17-11 H —C(O)NH— —CH₂C(O)N(OH)H) benzyl 17-12 H —C(O)NH— —CH₂C(O)N(OH)H)2-bromobenzyl 17-13 H —C(O)NH— —CH₂COOH benzyl 17-14 H —CH₂—NHC(O)——C(O)N(OH)H) —CH₂CH(CH₃)₂

(17-1)4-{2-butyl-4-chloro-5-[(2-mercaptomethyl-4-methylpentanoylamino)methyl]imidazol-1-ylmethyl}-naphthalene-1-carboxylicacid. MS m/z: [M+H⁺] calcd for C₂₇H₃₄ClN₃O₃S, 516.20. found 517.2.

(17-2)4-{2-butyl-4-chloro-5-[(2-mercaptomethyl-3-phenylpropionylamino)methyl]imidazol-1-ylmethyl}-naphthalene-1-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₀H₃₂ClN₃O₃S, 550.19. found 551.2.

(17-3)4-{2-butyl-4-chloro-5-[(2-mercaptomethyl-3-methylbutyrylamino)methyl]imidazol-1-ylmethyl}-naphthalene-1-carboxylicacid. MS m/z: [M+H⁺] calcd for C₂₆H₃₂ClN₃O₃S, 502.19. found 502.2.

(17-4)4-(5-{[2-(2-benzyl-3-mercaptopropionylamino)acetylamino]methyl}-2-butyl-4-chloroimidazol-1-ylmethyl)naphthalene-1-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₂H₃₅ClN₄O₄S, 607.21. found 607.2.

(17-5)4-{2-butyl-4-chloro-5-[(2-hydroxycarbamoyl-4-methylpentanoylamino)methyl]imidazol-1-ylmethyl}naphthalene-1-carboxylicacid. MS m/z: [M+H⁺] calcd for C₂₇H₃₃ClN₄O₅, 529.21. found 529.2.

(17-6)4-{2-butyl-4-chloro-5-[(2-hydroxycarbamoyl-3-methylbutyrylamino)methyl]imidazol-1-ylmethyl}naphthalene-1-carboxylicacid. MS m/z: [M+H⁺] calcd for C₂₆H₃₁ClN₄O₅, 515.20. found 515.2.

(17-7)4-[2-butyl-5-(1-hydroxycarbamoylmethyl-3-methylbutylcarbamoyl)imidazol-1-ylmethyl]naphthalene-1-carboxylicacid. MS m/z: [M+H⁺] calcd for C₂₇H₃₄N₄O₅, 495.25. found 495.4.

(17-8)4-[2-butyl-4-chloro-5-((S)-1-hydroxycarbamoyl-2-phenylethylcarbamoyl)imidazol-1-ylmethyl]naphthalene-1-carboxylic acid. MS m/z: [M+H⁺] calcdfor C₂₉H₂₉ClN₄O₅, 549.18. found 549.2.

(17-9)4-[2-butyl-5-(1-hydroxycarbarnoylmethyl-2-phenylethylcarbamoyl)imidazol-1-ylmethyl]naphthalene-1-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₀H₃₂N₄O₅, 529.24. found 529.4.

(17-10)4-[2-butyl-4-chloro-5-(1-hydroxycarbamoylmethyl-2-phenylethylcarbamoyl)imidazol-1-ylmethyl]naphthalene-1-carboxylic acid. MS m/z: [M+H⁺] calcdfor C₃₀H₃₁ClN₄O₅, 563.20. found 563.4.

(17-11)4-[2-butyl-5-((R)-1-hydroxycarbamoylmethyl-2-phenylethylcarbamoyl)imidazol-1-ylmethyl]naphthalene-1-carboxylic acid. MS m/z: [M+H⁺] calcdfor C₃₀H₃₂N₄O₅, 529.24. found 529.5.

(17-12)4-{5-[(R)-2-(2-bromophenyl)-1-hydroxycarbamoylmethylethylcarbamoyl]-2-butylimidazol-1-ylmethyl}naphthalene-1-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₀H₃₁BrN₄O₅, 607.15. found 608.2.

(17-13)4-[2-butyl-5-((R)-1-carboxymethyl-2-phenylethylcarbamoyl)imidazol-1-ylmethyl]naphthalene-1-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₀H₃₁N₃O₆, 514.23; found 514.2.

(17-14)4-{2-butyl-5-[(2-hydroxycarbamoyl-4-methylpentanoylamino)methyl]imidazol-1-ylmethyl}naphthalene-1-carboxylicacid. MS m/z: [M+H⁺] calcd for C₂₇H₃₄N₄O₅ 495.25. found 495.2.

Example 18

Following the procedures described in the examples above, andsubstituting the appropriate starting materials and reagents, thefollowing compound was also prepared:

(4-{2-butyl-4-chloro-5-[(2-hydroxycarbamoyl-4-methylpentanoylamino)methyl]imidazol-1-ylmethyl}phenoxy)phenylaceticacid. MS m/z: [M+H⁺] calcd for C₃₀H₃₇ClN₄O₆, 585.24. found 585.4.

Preparation 13 5-Bromo-2-ethoxy-3H-imidazole-4-carbaldehyde

2,4,5-Tribromo-1H-imidazole (13a) (98.7 g, 324 mmol, 1.0 eq) wasdissolved into 1.20 L of methylene chloride and cooled to 0° C. To thiswas added DIPEA (62 mL, 360 mmol, 1.1 eq) followed by the slow additionof β-(trimethylsilyl)ethoxy)methyl chloride (60.2 mL, 340 mmol, 1.05eq). The solution was slowly warmed to room temperature. After 2 hoursthe mixture was washed 2× with 600 mL of 1M H₃PO₄/saturated aqueous NaCl(1/10 mL). The organic layer was dried over MgSO₄, and evaporated todryness, yielding intermediate (13b) as faint yellow liquid thatsolidified on standing (137 g).

Intermediate (13b) (130 g, 290 mmol, 1.0 eq) was dissolved into 650 mLanhydrous ethanol. To this was slowly added potassium tert-butoxide(98.6 g, 879 mmol, 3.0 eq) and the mixture was heated to reflux for 16hours. The mixture was then cooled to room temperature, filtered andconcentrated. The resulting oil was dissolved into 800 mL EtOAc andwashed with 400 mL saturated NaHCO₃. The layers were separated and theorganic was washed with saturated aqueous NaCl, dried over MgSO₄,filtered and concentrated, yielding intermediate (13c) as a brown oil(115.3 g). MS m/z: [M+H⁺] calcd for C₁₁H₂₀Br₂N₂O₂Si, 401.9 found 401.2.,

Intermediate (13c) (69.5 g, 174 mmol, 1.0 eq) was dissolved in 600 mL ofanhydrous THF and cooled to −78° C. under nitrogen. A 2.5 M solution ofn-butyllithium in hexanes (72.9 mL, 180 mmol, 1.05 eq) was addeddropwise and the mixture was stirred at −78° C. for 10 minutes. DMF (40mL, 520 mmol, 3.0 eq) was then added and the mixture was stirred at −78°C. for 15 minutes and was then warmed to room temperature. The reactionwas quenched with 10 mL water, diluted with 600 mL EtOAc and was washedwith 100 mL water, saturated aqueous NaCl, dried over MgSO₄ andconcentrated under reduced pressure. The recovered material was purifiedby silica gel chromatography (15-30% EtOAc:hexanes) to produceintermediate (13d) as a pale yellow oil (45 g).

Intermediate (13d) (105.8 g, 303 mmol, 1.0 eq) was cooled at 0° C. inice. TFA (300 mL) was added and the mixture was stirred at 0° C. for 15minutes, then warmed to room temperature. After 90 minutes the mixturewas concentrated under reduced pressure and redissolved in 700 mL EtOAc.The organic was washed 2×600 mL saturated bicarbonate, saturated aqueousNaCl, dried over MgSO₄, and concentrated under reduced pressure toproduce a yellow solid. The material was suspended in 300 mL hexane andstirred at 0° C. for 30 minutes. The material was filtered and the solidwas washed with 150 mL of cold hexane to yield the title compound as apale white solid (61.2 g). ¹H-NMR (CDCl₃) δ (ppm): 1.4 (m, 3H), 4.5 (m,2H), 5.2 (s, 1H), 9.2 (d, 1H).

Preparation 14 4′-Bromomethyl-3′-fluorobiphenyl-2-carboxylic Acidt-Butyl Ester

To a solution of 1.0 M DCC in methylene chloride (505 mL, 505 mmol, 1.0eq) cooled at 0° C. was added 2-bromobenzoic acid (14a) (101.6 g, 505mmol, 1.0 eq) followed by DMAP (5.7 g, 470 mmol, 0.09 eq) and t-butylalcohol (53.2 mL, 560 mmol, 1.1 eq). The mixture was stirred at roomtemperature for 18 hours and was then filtered. The organic was washedwith 400 mL saturated NaHCO₃, saturated aqueous NaCl, dried over MgSO₄,filtered and concentrated to produce the crude intermediate (14b) as anoil (141.8 g).

The crude intermediate (14b) (111.2 g, 433 mmol 1.0 eq) and3-fluoro-4-methylphenylboronicacid (73.2 g, 476 mmol, 1.1 eq) weresuspended in isopropyl alcohol (370 mL). A 2.0 M solution of sodiumcarbonate in water (370 mL) was added and the mixture was degassed undernitrogen. Tetrakis(triphenylphosphine)palladium(0) (5.0 g, 4.3 mmol,0.01 eq) was then added and the mixture was stirred at 90° C. for 46hours. The mixture was cooled to room temperature, diluted with 800 mLEtOAc, and the layers were separated. The organic was washed withsaturated aqueous NaCl and concentrated under reduced pressure. Therecovered oil was purified by silica gel chromatography (4-6%EtOAc:hexanes) to yield intermediate (14c) as an oil (97.4 g).

Intermediate (14c) (89.8 g, 314 mmol, 1.0 eq) was dissolved in CCl₄ (620mL) and was degassed under nitrogen. NBS (55.8 g, 314 mmol, 1.0 eq) wasadded, followed by benzoyl peroxide (1.5 g, 6.3 mmol, 0.02 eq) and themixture was heated at 90° C. under nitrogen for 16 hours. The reactionwas cooled in an ice bath, filtered, and concentrated under reducedpressure. The recovered oil was triturated with 150 mL of 3%EtOAc:hexanes. The solution was chilled at −20° C. for 2 hours, thenfiltered and washed with 200 mL cold 3% EtOAc:hexanes solution to yieldthe title compound as an off white solid (88.9 g). ¹H-NMR (CDCl₃) δ(ppm): 1.3 (m, 9H), 4.6 (s, 2H), 7.0-7.1 (m, 2H), 7.3 (dd, 1H), 7.4 (m,1H), 7.5 (m, 1H), 7.8 (dd, 1H).

Preparation 154′-(5-Aminomethyl-2-ethoxy-4-ethylimidazol-1-ylmethyl)-3′-fluorobiphenyl-2-carboxylicAcid t-Butyl Ester

4′-(4-Bromo-2-ethoxy-5-formylimidazol-1-ylmethyl)-3′-fluorobiphenyl-2-carboxylicacid t-butyl ester (15a): 5-Bromo-2-ethoxy-3H-imidazole-4-carbaldehyde(15.0 g, 68.5 mmol), 4′-bromomethyl-3′-fluorobiphenyl-2-carboxylic acidt-butyl ester (25.0 g, 68.5 mmol) and potassium carbonate (9.5 g, 68.5mmol) were dissolved in DMF (958 mL, 12.4 mol) and was stirred at roomtemperature for 2 hours. The reaction was quenched with water, and themixture extracted with EtOAc, washed with saturated aqueous NaCl, driedover MgSO₄, filtered and concentrated in vacuo. The mixture was purifiedby silica gel chromatography (0-30% EtOAc:hexanes) to yield intermediate(15a) (25 g). MS m/z: [M+H⁺] calcd for C₂₄H₂₄BrFN₂O₄, 503.3. found503.2. ¹H-NMR (CDCl₃): 9.57 (1H, s), 7.80 (1H, d), 7.48 (2H, m), 7.27(1H, s), 7.11 (1H, t), 7.01 (2H, d), 5.47 (2H, s), 4.33 (2H, q), 1.41(3H, t), 1.24 (9H, s).

4′-(2-Ethoxy-5-formyl-4-vinylimidazol-1-ylmethyl)-3′-fluorobiphenyl-2-carboxylicacid t-butyl ester (15b): Intermediate (15a) (11.0 g, 21.8 mmol) wasdissolved in 1,2-dimethoxyethane (100 mL, 1 mol).Tetrakis(triphenylphosphine)palladium(0) (252 mg, 218 μmol) was addedand the mixture was stirred under nitrogen for 20 minutes. Water (48 mL,2.6 mol), 2,4,6-trivinylcyclotriboroxane pyridine complex (2.1 g, 8.7mmol) and potassium carbonate (3.0 g, 21.8 mmol) were then added and themixture was heated at 90° C. under nitrogen. After 2 hours, the mixturewas cooled to room temperature, diluted with EtOAc, washed with waterand saturated aqueous NaCl, dried over MgSO₄, filtered, and concentratedin vacuo. The mixture was purified by silica gel chromatography (0-50%EtOAc:hexanes) to yield intermediate (15b) (9.8 g). MS m/z: [M+H⁺] calcdfor C₂₆H₂₇FN₂O₄, 451.2. found 451.0. ¹H-NMR (CDCl₃): 8.17 (1H, s), 7.79(1H, d), 7.48 (1H, t), 7.40 (1H, t), 7.28 (1H, s), 7.01 (2H, m), 6.86(1H, t), 6.67 (1H, m), 5.95 (1H, d), 5.41 (2H, s), 5.27 (1H, d), 4.48(2H, q), 1.38 (3H, t), 1.25 (9H, s).

4′-[2-Ethoxy-5-(hydroxyiminomethyl)-4-vinylimidazol-1-ylmethyl]-3′-fluorobiphenyl-2-carboxylicacid t-butyl ester (15c): Intermediate (15b) (19.5 g, 43.4 mmol) wasdissolved in pyridine (100 mL, 1 mol). Hydroxylamine hydrochloride (9.0g, 130 mmol) was added, followed by water (50 mL, 3 mol), and themixture was stirred at room temperature overnight. Water (100 mL) wasthen added and the mixture was stirred for 20 minutes. The precipitantwas filtered off and dried to yield intermediate (15c) (13.5 g). MS m/z:[M+H⁺] calcd for C₂₆H₂₈FN₃O₄, 466.2. found 466.4. ¹H-NMR (CDCl₃): 9.78(1H, s), 7.81 (1H, d), 7.48 (2H, m), 7.26 (1H, s), 7.0 (4H, m), 6.20(1H, d), 5.53 (1H, d), 5.50 (2H, s), 4.55 (2H, q), 1.43 (3H, t), 1.25(9H, s).

Intermediate (15c) (4.0 g, 8.6 mmol) was dissolved in ethanol (250 mL,4.3 mol) and sulfuric acid (0.50 mL, 9.4 mmol), and subjected tosonication. Once fully dissolved, the mixture was added to 10% Pd/C,Degussa type, wet 50% (0.05:0.45:0.5, palladium:carbon black:water, 3.0g, 1.4 mmol) in 20 ml of ethanol. The solution was degassed and stirredat room temperature under hydrogen for 5 hours. The palladium wasfiltered off and the mixture was concentrated to yield the titlecompound (3.3 g). MS m/z: [M+H⁺] calcd for C₂₆H₃₂FN₃O₃, 454.3. found454.2. ¹H-NMR (CDCl₃): 7.82 (1H, d), 7.50 (1H, t), 7.42 (1H, t) 7.35(1H, d), 7.27 (1H, d), 7.12 (1H, s), 7.04 (1H, d), 5.34 (1H, b), 4.65(2H, s), 4.40 (2H, q), 4.12 (2H, q), 2.70 (1H, b), 1.50 (3H, t), 1.28(9H, s), 1.17 (3H, t).

Alternate Synthesis of Intermediate (15a)

5-Bromo-2-ethoxy-3H-imidazole-4-carbaldehyde (19.8 g, 90.6 mmol), and4′-bromomethyl-3′-fluorobiphenyl-2-carboxylic acid t-butyl ester (33.1g, 90.6 mmol) were dissolved in DMF (400 mL). The mixture was cooled inan ice bath and potassium carbonate (12.5 g, 90.6 mmol) was added over 5minutes. The temperature was slowly warmed overnight. The reaction wasthen quenched with water. The mixture was extracted with 300 mL EtOAc,washed with saturated aqueous NaCl, dried over MgSO4, filtered, andconcentrated. The product was purified by silica gel chromatography(0-30% EtOAc:hexanes) to obtain intermediate (15a) as a white solid(34.2 g). MS m/z: [M+H⁺] calc'd for C₂₄H₂₄BrFN₂O₄, 503.3. found 503.2.¹H NMR (CDCl₃) 9.57 (1H, s), 7.80 (1H, d), 7.48 (2H, m), 7.27 (1H, s),7.11 (1H, t), 7.01 (2H, d), 5.47 (2H, s), 4.33 (2H, q), 1.41 (3H, t),1.24 (9H, s).

Alternate Synthesis of Title Compound

Intermediate (15c) (4.5 g, 9.7 mmol) was dissolved in acetic acid (100mL, 2000 mmol) and stirred for 10 minutes at room temperature. Zinc dust(5.9 g, 90.2 mmol) was then added and the mixture was stirred for 45minutes. The zinc was filtered off and the acetic acid was concentrated.The residue was taken up in EtOAc and washed with sodium bicarbonate andsaturated aqueous NaCl. The organic layer was dried over MgSO₄,filtered, and concentrated in vacuo. The residue was added to 10% Pd/C,Degussa type, wet 50% (0.05:0.45:0.5, palladium:carbon black:water, 400mg, 0.2 mmol) in ethanol (200 mL, 3 mol). The mixture was degassed andstirred under hydrogen for 1.5 hours. The palladium was filtered off andthe solvent was concentrated to obtain the title compound (4.6 g). MSm/z: [M+H⁺] calcd for C₂₆H₃₂FN₃O₃, 454.3. found 454.2. ¹H-NMR (CDCl₃):7.82 (1H, d), 7.50 (1H, t), 7.42 (1H, t) 7.35 (1H, d), 7.27 (1H, d),7.12 (1H, s), 7.04 (1H, d), 5.34 (1H, b), 4.65 (2H, s), 4.40 (2H, q),4.12 (2H, q), 2.70 (1H, b), 1.50 (3H, t), 1.28 (9H, s), 1.17 (3H, t).

Alternate Synthesis of Title Compound

Intermediate (15c) (5.1 g, 11 mmol) was dissolved in acetic acid (100mL) and sulfuric acid (640 μL, 12 mmol). The mixture was degassed undernitrogen and 10% Pd/C, Degussa type, wet 50% (0.05:0.45:0.5,palladium:carbon black:water, 1.5 g, 723 μmol) was added. The mixturewas then degassed under hydrogen at 50 psi on a Parr shaker and shakenat room temperature. After 12 hours, the mixture was filtered andconcentrated under reduced pressure. The recovered material wasdissolved into 50 mL EtOAc, washed with 50 mL saturated bicarbonate,saturated aqueous NaCl, and evaporated. The material was purified bysilica gel chromatography (0-10% MeOH:DCM) to yield the title compoundas a clear oil (4.6 g). MS m/z: [M+H⁺] calc'd for C₂₆H₃₂FN₃O₃, 454.3.found 454.2. ¹H NMR (CDCl₃) 7.82 (1H, d), 7.50 (1H, t), 7.42 (1H, t)7.35 (1H, d), 7.27 (1H, d), 7.12 (1H, s), 7.04 (1H, d), 5.34 (1H, b),4.65 (2H, s), 4.40 (2H, q), 4.12 (2H, q), 2.70 (1H, b), 1.50 (3H, t),1.28 (9H, s), 1.17 (3H, t).

Example 194′-{5-[((S)-2-Acetylsulfanyl-4-methylpentanoylamino)methyl]-2-ethoxy-4-ethylimidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicAcid t-Butyl Ester (19a; R^(1a)=t-butyl; R^(5a)=—C(O)CH₃);4′-{5-[((S)-2-Acetylsulfanyl-4-methylpentanoylamino)methyl]-2-ethoxy-4-ethylimidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicAcid (19b; R^(1a)H; R^(5a)=—C(O)CH₃); and4′-{2-Ethoxy-4-ethyl-5-[((S)-2-mercapto-4-methylpentanoylamino)methyl]-imidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicAcid (19c; R^(1a)═H; R^(5a)═H)

(S)-2-Acetylsulfanyl-4-methylpentanoic acid (877 mg, 4.6 mmol) wasdissolved in DMF (20 mL, 300 mmol). HATU (1.8 g, 4.6 mmol) and DIPEA(0.8 mL, 4.6 mmol) were added and the mixture was stirred at roomtemperature for 30 minutes.4′-(5-Aminomethyl-2-ethoxy-4-ethylimidazol-1-ylmethyl)-3′-fluorobiphenyl-2-carboxylicacid t-butyl ester (1.9 g, 4.2 mmol) in DMF (20 mL, 300 mmol) with DIPEA(0.8 mL, 4.6 mmol) was added, and the mixture was stirred at roomtemperature for 2 hours. The reaction was quenched with water, extractedwith EtOAc, washed with saturated aqueous NaCl, dried over MgSO₄,filtered and concentrated. The mixture was purified by silica gelchromatography (0-50% EtOAc:hexanes) to obtain to obtain theacetylsulfanyl ester intermediate (19a) (2.4 g). MS m/z: [M+H⁺] calcdfor C₃₄H₄₄FN₃O₅S, 626.3. found 626.2. ¹H-NMR (CDCl₃): 7.80 (1H, d), 7.48(1H, t), 7.40 (1H, t), 7.25 (1H, d), 7.06 (2H, d), 6.88 (1H, t), 6.08(1H, t), 4.96 (2H, s), 4.38 (2H, q), 4.22 (2H, m), 3.86 (1H, t), 2.50(2H, q), 2.32 (3H, s), 1.82 (1H, m), 1.64 (1H, m), 1.52 (1H, m), 1.34(3H, t), 1.26 (9H, s), 1.18 (3H, t), 0.87 (6H, dd).

Intermediate (19a) was dissolved in DCM:TFA (1:1) (5 mL each) andstirred at room temperature for 3 hours, then concentrated and carriedforward to provide the acetylsulfanyl acid intermediate (19b). MS m/z:[M+H⁺] calcd for C₃₀H₃₆FN₃O₅S, 570.2. found 570.4. ¹H-NMR (DMSO): 8.64(1H, b), 7.72 (1H, d), 7.55 (1H, t), 7.44 (1H, t), 7.33 (1H, d), 7.16(1H, d), 7.07 (1H, d), 6.95 (1H, b), 5.05 (2H, s), 4.35 (2H, d), 4.12(2H, t), 40.5 (2H, t), 2.26 (3H, s), 1.64 (1H, m), 1.40 (2H, m), 1.28(3H, t), 1.10 (3H, t), 0.80 (6H, dd).

Intermediate (19b) was dissolved in MeOH (20 ml), and 10N NaOH (2 ml)was added. The mixture was stirred at room temperature for 25 minutesunder nitrogen before the reaction was quenched with acetic acid and themixture concentrated. The resulting material was purified by preparativeHPLC (10-70%) to obtain the final product (19c) as a TFA salt (1.6 g;98% pure). MS m/z: [M+H⁺] calcd for C₂₈H₃₄FN₃O₄S, 528.2. found 528.2.¹H-NMR (DMSO): 8.40 (1H, s), 7.74 (1H, d), 7.57 (1H, t), 7.47 (1H, t),7.35 (1H, d), 7.18 (1H, d), 7.09 (1H, d), 7.02 (2H, b), 5.11 (2H, s),4.40 (2H, d), 4.18 (2H, d), 3.28 (1H, q), 2.68 (1H, d), 2.48 (1H, d),1.58 (2H, m), 1.44 (1H, m), 1.26 (3H, t), 1.14 (3H, t), 0.79 (6H, dd).

Alternate Synthesis of Title Compound (19c)

Alternately, intermediate (19a) was obtained by the following procedure:To a cold solution of4′-(5-aminomethyl-2-ethoxy-4-ethylimidazol-1-ylmethyl)-3′-fluorobiphenyl-2-carboxylicacid t-butyl ester (1.2 g, 2.7 mmol) dissolved in DCM (45 mL) cooledwith an ice-salt bath (−5° C.) was added(S)-2-acetylsulfanyl-4-methylpentanoic acid (chiral purity 97.3% S: 531mg, 2.8 mmol) in 5 mL of DCM and EDC (535 mg, 2.8 mmol). The mixture wasstirred at −5° C. for 1 hour under nitrogen. The reaction was quenchedby adding a mixture of 1M H₃PO₄ and saturated aqueous NaCl (1:3; 50 mL),and diluted with DCM (200 mL). After shaking in a separatory funnel, theorganic layer was collected and washed with sat NaHCO₃. After dryingover MgSO₄, the organic layer was evaporated to dryness, yieldingintermediate (19a) as a pale yellow oil. The crude product (2.1 g) wasused in next step without further purification. ESMS [M+H⁺] calcd forC₃₄H₄₄FN₃O₅S, 626.31. found 626.4. Anal. HPLC retention time=3.62 min;gradient conditions=25-95% MeCN/H₂O over 5 min. Full deprotection ofboth the t-butyl ester and mercaptoacetyl group by treating with TFA/DCM(2:1), for 1 hour at room temperature and 1M NaOH in MeOH, for 5 minutesat room temperature in two separate steps afforded the final product(19c) as a TFA salt. Its chiral purity was determined to be 97.1% Ssingle isomer by anal. HPLC on chiral stationary phase.

Alternate Synthesis of Title Compound (19c)

4′-(5-Aminomethyl-2-ethoxy-4-ethylimidazol-1-ylmethyl)-3′-fluorobiphenyl-2-carboxylicacid t-butyl ester (4.0 g, 8.8 mmol),(S)-2-acetylsulfanyl-4-methylpentanoic acid (1.7 g, 8.8 mmol),4-methylmorpholine (970 μL, 8.82 mmol), and 1-hydroxy-7-azabenzotriazole(1.2 g, 8.8 mmol) were combined in a flask and dissolved in DMF (100 mL,1.300 mol) and was cooled at 0° C. for 10 minutes. Then EDC (1.6 mL, 8.8mmol) was added and the mixture was stirred at 0° C. for 1 hour and thenat room temperature for 1 hour and 15 minutes. The reaction was quenchedwith water (100 mL) and extracted with EtOAc (100 mL) and wasconcentrated. The mixture was purified by column chromatography (0-50%EtOAc:hexanes) to obtain 4.2 g of intermediate (19a). Intermediate (19a)was dissolved in DCM:TFA (10 mL each) and the mixture was stirred atroom temperature for 3 hours, and then concentrated. The residue wastaken up in EtOAc, washed with a saturated NaHCO₃ solution, dried overMgSO₄, and concentrated to yield 3.7 g of intermediate (19b).Intermediate (19b) was dissolved in 30 mL of MeOH. The solution wasdegassed, stirred under nitrogen, and cooled at 0° C. 25 mL of 0.5 Msodium methoxide in MeOH (2 eq.) was added and the mixture was stirredat 0° C. under nitrogen for 20 minutes. The mixture was then acidifiedwith 1N HCl (15 mL). The mixture was concentrated, dissolved in EtOAc,washed with water, dried over MgSO₄, filtered, and then concentrated.The product was purified by preparative HPLC 10-70% MeCN:water with 0.5%TFA (70 minute method). The product was dissolved in ˜4 mL of MeCN, 3 mLof water and 0.5 mL of TFA to be injected on the column. 2 g of thefinal product (19c) was isolated as 98% pure, 93.6% ee.

Synthesis of Title Compound (19c) as a HCl Salt

The title compound (19c) was also obtained as an HCl salt as follows.Preparation of ion exchange column: Forty grams of amberlite IRA-900resin (Aldrich) was suspended in 400 mL of 1M HCl. The mixture wasshaken for 60 minutes and the bulk of the supernatant was decanted toafford wet resins, which were then transferred to a 100 mL plasticcolumn. A small amount of sand was added to the top layer of the resin.The column was washed by elution with water (200 mL) and 50% aq. MeCN(200 mL) until the pH of the passed eluant was ˜5. The TFA salt of4′-{2-ethoxy-4-ethyl-5-[((S)-2-mercapto-4-methylpentanoyl-amino)methyl]imidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicacid (945 mg) was dissolved in 50% aq. MeCN (5 mL), and loaded onto theprepared column. The compound was eluted with 50% aq. MeCN undergravity. Fractions were collected in 5 mL volume, and analyzed by HPLC,and LCMS. Fractions having the desired mass were combined andlyophilized, affording the title compound (19c) as a HCl salt (700 mg).Analysis of the ion content of the salt using ion chromatography gave7.1% Cl (w/w).

Preparation of the (R) Enantiomer of Title Compound (19c)

The (R) enantiomer of the title compound (19c) was obtained by thefollowing procedure.

4′-{5-[((R)-2-Acetylsulfanyl-4-methylpentanoylamino)methyl]-2-ethoxy-4-ethylimidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicacid t-butyl ester (19a′):4′-(5-Aminomethyl-2-ethoxy-4-ethylimidazol-1-ylmethyl)-3′-fluorobiphenyl-2-carboxylicacid t-butyl ester (128 mg, 282 μmol),(R)-2-acetylsulfanyl-4-methylpentanoic acid (53.7 mg, 282 μmol),1-hydroxy-7-azabenzotriazole (38.4 mg, 282 μmol), and 4-methylmorpholine(31.0 μL, 282 μmol) were combined and dissolved in DMF (2.5 mL, 32.3mmol) and cooled at 0° C. for 10 minutes. EDC (50.0 μL, 282 μmol) wasadded. After 20 minutes, the mixture was warmed to room temperature. Thereaction was complete after 90 minutes, as determined by HPLC and LCMS,and water (5 mL) was added. The mixture was extracted 2× with EtOAc,washed with 1N HCl (10 mL), water, and saturated aqueous NaCl, driedover MgSO4, filtered, and concentrated to yield a yellow oil (164 mg).This material was purified by silica gel chromatography (12 g, 0-100%EtOAc:hexanes) to yield a first lot of the acetylsulfanyl esterintermediate (19a′) as a colorless oil (46 mg).

4′-(5-Aminomethyl-2-ethoxy-4-ethylimidazol-1-ylmethyl)-3′-fluorobiphenyl-2-carboxylicacid t-butyl ester (120.0 mg, 265 μmol) and(R)-2-acetylsulfanyl-4-methylpentanoic acid (50.3 mg, 264 μmol) weredissolved in methylene chloride (2.0 mL, 31.2 mmol) and cooled at 0° C.for 10 minutes. EDC (46.8 μL, 264 μmol) was added. The mixture waswarmed to room temperature over 2 hours. The mixture was then cooled at0° C. and DIPEA (46.1 μL, 264 μmol) was added. This mixture was stirredat 0° C. for 5 minutes then warmed to room temperature. After 30minutes, water (5 mL) was added. The mixture was extracted 2× with DCM,washed with saturated aqueous NaCl, dried over MgSO4, filtered, andconcentrated to yield a yellow oil (164 mg). This material was purifiedby silica gel chromatography (12 g, 0-100% EtOAc:hexanes) to provide asecond lot of the acetylsulfanyl ester intermediate (19a′) as acolorless oil (68 mg).

4′-{5-[((R)-2-acetylsulfanyl-4-methylpentanoylamino)methyl]-2-ethoxy-4-ethylimidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicacid (19b′): The combined lots of Intermediate (19a′) (114 mg, 182 μmol)were dissolved in methylene chloride (2.0 mL, 31 mmol). TFA (2.0 mL, 26mmol) was added. After 60 minutes, the mixture was concentrated. Sat.bicarbonate (5 mL) was added and the mixture was extracted 3× withEtOAc, washed with saturated aqueous NaCl, dried over MgSO4, filtered,and concentrated to provide 90 mg of the crude the acetylsulfanyl acidintermediate (19b′).

Intermediate (19b′) was taken up in MeOH (2.0 mL) and cooled at 0° C.under nitrogen. 0.50 M of Sodium methoxide in MeOH (729 μL, 364 μmol)was added. After 30 minutes, the mixture was acidified with 6N HCl (90μL) and concentrated. The product was purified by preparative HPLC toyield4′-{2-ethoxy-4-ethyl-5-[((R)-2-mercapto-4-methylpentanoylamino)methyl]-imidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicacid as a white solid TFA salt (59.4 mg; 96.0% purity). The product wasanalyzed for chiral purity and found to be 99% ee. MS m/z: [M+H⁺] calcdfor C₂₈H₃₄FN₃O₄S, 528.23. found 528.2.

Preparation 164′-(5-Aminomethyl-2-ethoxy-4-ethylimidazol-1-ylmethyl)-3′-fluorobiphenyl-2-carboxylicAcid t-Butyl Ester

4′-(4-Bromo-2-ethoxy-5-formylimidazol-1-ylmethyl)-3′-fluorobiphenyl-2-carboxylicacid t-butyl ester (16a): 5-Bromo-2-ethoxy-3H-imidazole-4-carbaldehyde(6.0 g, 27.4 mmol), 4′-bromomethyl-3′-fluorobiphenyl-2-carboxylic acidt-butyl ester (10.0 g, 27.4 mmol), and potassium carbonate (3.8 g, 27.4mmol) were dissolved in DMF (383 mL, 4950 mmol) and the mixture wasstirred at room temperature for 2 hours. The reaction was quenched withwater, and the mixture was extracted with EtOAc, washed with saturatedaqueous NaCl, dried over MgSO₄, filtered, and concentrated. Theresulting material was purified by silica gel chromatography (0-30%EtOAc:hexanes) to yield intermediate (16a) (9.5 g). MS m/z: [M+H⁺] calcdfor C₂₄H₂₄BrFN₂O₄, 503.3. found 503.2. ¹H-NMR (CDCl₃): 9.57 (1H, s),7.80 (1H, d), 7.48 (2H, m), 7.27 (1H, s), 7.11 (1H, t), 7.01 (2H, d),5.47 (2H, s), 4.33 (2H, q), 1.41 (3H, t), 1.24 (9H, s).

4′-(2-Ethoxy-5-formyl-4-vinylimidazol-1-ylmethyl)-3′-fluorobiphenyl-2-carboxylicacid t-butyl ester (16b): Intermediate (16a) (9.5 g, 18.9 mmol),tetrakis(triphenylphosphine) palladium(0) (1.0 g, 0.9 mmol),(2-ethenyl)tri-n-butyltin (11.0 mL, 37.8 mmol) were dissolved in DMF (70mL, 900 mmol), and heated at 90° C. for 1.5 hours. The mixture wascooled to room temperature and 300 mL of EtOAc was added. The organiclayer was washed using a 20% potassium fluoride solution (2×100 mL) andsaturated aqueous NaCl. The resulting material was purified by silicagel chromatography (0-60% EtOAc:hexanes) to yield intermediate (16b)(7.7 g). MS m/z: [M+H⁺] calcd for C₂₆H₂₇FN₂O₄, 451.2. found 451.0.¹H-NMR (CDCl₃): 8.17 (1H, s), 7.79 (1H, d), 7.48 (1H, t), 7.40 (1H, t),7.28 (1H, s), 7.01 (2H, m), 6.86 (1H, t), 6.67 (1H, m), 5.95 (1H, d),5.41 (2H, s), 5.27 (1H, d), 4.48 (2H, q), 1.38 (3H, t), 1.25 (9H, s).

4′-[2-Ethoxy-5-(hydroxyiminomethyl)-4-vinylimidazol-1-ylmethyl]-3′-fluorobiphenyl-2-carboxylicacid t-butyl ester (16c): Intermediate (16b) (7.7 g, 17.2 mmol) wasdissolved in pyridine (40 mL, 500 mmol). Hydroxylamine hydrochloride(3.6 g, 51.5 mmol) was added, followed by the addition of water (20 mL,1 mol). The mixture was stirred at room temperature overnight. Water (50ml) was added and the mixture was stirred for 20 minutes. Theprecipitant was filtered off and dried to yield intermediate (16c) (7.8g). MS m/z: [M+H⁺] calcd for C₂₆H₂₈FN₃O₄, 466.2. found 466.4. ¹H-NMR(CDCl₃): 9.78 (1H, s), 7.81 (1H, d), 7.48 (2H, m), 7.26 (1H, s), 7.0(4H, m), 6.20 (1H, d), 5.53 (1H, d), 5.50 (2H, s), 4.55 (2H, q), 1.43(3H, t), 1.25 (9H, s).

4′-[2-Ethoxy-4-ethyl-5-(hydroxyiminomethyl)imidazol-1-ylmethyl]-3′-fluorobiphenyl-2-carboxylicacid t-butyl ester (16d): Intermediate (16c) (7.8 g, 16.6 mmol) wasdissolved in ethanol (420 mL, 7.2 mol). Pearlman's Catalyst, wet(0.1:0.4:0.5, palladium hydroxide:carbon black:water, 6 g, 4 mmol) wasadded. The mixture was degassed and stirred under hydrogen for 2 hours.The palladium was filtered off and the solvent was concentrated to yieldintermediate (16d) (7.7 g). MS m/z: [M+H⁺] calcd for C₂₆H₃₀FN₃O₄, 468.2.found 468.4.

Intermediate (16d) (7.9 g, 16.8 mmol), NaBH₃CN (4.8 g, 75.7 mmol) andammonium acetate (2.9 g, 37.0 mmol) were dissolved in MeOH. The mixturewas cooled to 0° C. and stirred for 15 minutes before titanium(III)chloride (7.8 g, 50.4 mmol) was added. The mixture was stirred at 0° C.for 10 minutes then warmed to room temperature and stirred for 4 hours.Ammonium hydroxide (75 mL) was added to quench the reaction and themixture was stirred at room temperature overnight. 75 ml of saturatedsodium bicarbonate was then added. The resulting mixture was extracted 4times with DCM, dried over MgSO₄, filtered, and concentrated. Theresulting material was purified by silica gel chromatography (0-10% MeOHin DCM) to obtain the title compound (4.7 g). MS m/z: [M+H⁺] calcd forC₂₆H₃₂FN₃O₃, 454.3. found 454.4. ¹H-NMR (CDCl₃): 7.82 (1H, d), 7.50 (1H,t), 7.42 (1H, t) 7.35 (1H, d), 7.27 (1H, d), 7.12 (1H, s), 7.04 (1H, d),5.34 (1H, b), 4.65 (2H, s), 4.40 (2H, q), 4.12 (2H, q), 2.70 (1H, b),1.50 (3H, t), 1.28 (9H, s), 1.17 (3H, t).

Example 204′-{5-[((S)-2-Acelsulfanylmethyl-4-methylpentanoylamino)methyl]-2-ethoxy-4-ethylimidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicAcid t-Butyl Ester (20a; R^(1a)=t-butyl; R^(5a)=—C(O)CH₃);4′-{5-[((S)-2-Acetylsulfanylmethyl-4-methylpentanoylamino)methyl]-2-ethoxy-4-ethylimidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicAcid (20b; R^(1a)═H; R^(5a)=—C(O)CH₃);4′-{2-Ethoxy-4-ethyl-5-[((S)-2-mercaptomethyl-4-methylpentanoylamino)methyl]imidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicAcid (20c; R^(1a)═H; R^(5a)═H)

(S)-2-Acetylsulfanylmethyl-4-methylpentanoic acid (2 g, 9.7 mmol) wasdissolved in DMF (100 mL, 1000 mmol). HATU (3.7 g, 9.7 mmol) and DIPEA(1.5 mL, 8.8 mmol) were added and the mixture was stirred at roomtemperature for 20 minutes.4′-(5-Aminomethyl-2-ethoxy-4-ethylimidazol-1-ylmethyl)-3′-fluorobiphenyl-2-carboxylicacid t-butyl ester (4.0 g, 8.8 mmol) in DMF (20 mL, 200 mmol) with DIPEA(1.5 mL, 8.8 mmol) was added and the mixture was stirred at roomtemperature overnight. The reaction was quenched with water, and themixture was extracted with EtOAc, washed with saturated aqueous NaCl,dried over MgSO₄, filtered, and concentrated to yield the acetylsulfanylester intermediate (20a). This intermediate was taken up in DCM:TFA (4mL each), stirred at room temperature for 4 hours, and then concentratedto yield the acetylsulfanyl acid intermediate (20b). This intermediatewas dissolved in 1:1 MeOH:1N NaOH (4 mL each) and stirred at roomtemperature under nitrogen for 1 hour before the reaction was quenchedwith acetic acid and the mixture concentrated. The residue was purifiedby preparative HPLC (10-70% MeCN in water w/0.05% TFA) to obtain thefinal product (20c) (2.8 g; 98% pure). MS m/z: [M+H⁺] calcd forC₂₉H₃₆FN₃O₄S, 542.2. found 542.4. ¹H-NMR (DMSO): 8.39 (1H, s), 7.75 (1H,d), 7.58 (1H, t), 7.45 (1H, t), 7.34 (1H, d), 7.19 (1H, d), 7.10 (2H,m), 5.16 (2H, s), 4.43 (2H, m), 4.18 (2H, m), 2.58 (2H, m), 2.41 (1H,m), 2.32 (2H, m), 2.10 (1H, t), 1.24 (8H, m), 0.78 (6H, dd).

Preparation 174′-(5-Aminomethyl-2-ethoxy-4-ethylimidazol-1-ylmethyl)-biphenyl-2-carboxylicAcid t-Butyl Ester

4′-(4-Bromo-2-ethoxy-5-formylimidazol-1-ylmethyl)biphenyl-2-carboxylicacid t-butyl ester (17a): 5-Bromo-2-ethoxy-3H-imidazole-4-carbaldehyde(3.0 g, 13.7 mmol), 4′-bromomethylbiphenyl-2-carboxylic acid t-butylester (4.8 g, 13.7 mmol), and potassium carbonate (1.9 g, 13.7 mmol),were dissolved in DMF (60 mL, 780 mmol), and the mixture was stirred atroom temperature overnight. The reaction was quenched with water, andthe mixture was extracted with EtOAc, washed with saturated aqueousNaCl, dried over MgSO₄, filtered, and concentrated. The resultingmaterial was purified by silica gel chromatography (0-30% EtOAc:hexanes)to yield intermediate (17a) (5.6 g). MS m/z: [M+H⁺] calcd forC₂₄H₂₅BrN₂O₄, 485.1. found 485.3. ¹H-NMR (CDCl₃): 9.58 (1H, s), 7.80(1H, d), 7.50 (1H, t), 7.40 (1H, t), 7.30 (5H, m), 5.42 (2H, s), 4.57(2H, q), 1.46 (3H, t), 1.18 (9H, s).

4′-(2-Ethoxy-5-formyl-4-vinylimidazol-1-ylmethyl)biphenyl-2-carboxylicacid t-butyl ester (17b): Intermediate (17a) (5.6 g, 11.5 mmol),tetrakis(triphenylphosphine) palladium(0) (2.1 g, 1.8 mmol), and(2-ethenyl)tri-n-butyltin (13.5 mL, 46.2 mmol) were dissolved in DMF (70mL, 900 mmol), and heated at 90° C. for 1.5 hours. The mixture wascooled to room temperature and 300 mL of EtOAc was added. The organiclayer was washed using a 20% potassium fluoride solution (2×100 mL) andsaturated aqueous NaCl. The resulting material was purified by silicagel chromatography (0-60% EtOAc:hexanes) to yield intermediate (17b)(4.3 g). MS m/z: [M+H⁺] calcd for C₂₆H₂₈N₂O₄, 433.2. found 433.4.

4′-[2-Ethoxy-5-(hydroxyiminomethyl)-4-vinylimidazol-1-ylmethyl]biphenyl-2-carboxylicacid t-butyl ester (17c): Intermediate (17b) (4.3 g, 10 mmol) wasdissolved in pyridine (40 mL, 500 mmol). Hydroxylamine hydrochloride(1.7 g, 25 mmol) was added, followed by the addition of water (20 mL,1000 mmol). The mixture was stirred at room temperature overnight. Water(30 mL) was added and the mixture was stirred for 20 minutes. Theprecipitant was filtered off and dried to yield intermediate (17c) (3.5g). MS m/z: [M+H⁺] calcd for C₂₆H₂₉N₃O₄, 448.2. found 448.3.

4′-[2-Ethoxy-4-ethyl-5-(hydroxyiminomethyl)imidazol-1-ylmethyl]biphenyl-2-carboxylicacid t-butyl ester (17d): Intermediate (17c) (3.5 g, 7.7 mmol) wasdissolved in ethanol (100 mL, 2 mol). Pearlman's Catalyst, wet(0.1:0.4:0.5, palladium hydroxide:carbon black:water, 660 mg) was added.The mixture was degassed and stirred at room temperature under hydrogenfor 3 hours. The palladium was filtered off and the solute wasconcentrated to yield intermediate (17d) (3.3 g). MS m/z: [M+H⁺] calcdfor C₂₆H₃₁N₃O₄, 450.2. found 450.3.

Intermediate (17d) (3.5 g, 7.7 mmol), NaBH₃CN (1.9 g, 30.5 mmol) andammonium acetate (1150 mg, 14.9 mmol) were dissolved in MeOH (30 mL, 700mmol). The mixture was cooled at 0° C. and stirred for 15 minutes beforetitanium(III) chloride (3.1 g, 20.3 mmol) was added. The mixture wasstirred at 0° C. for 10 minutes then warmed to room temperature andstirred for 3 hours. Ammonium hydroxide (75 ml) was added and themixture was stirred at room temperature overnight. 75 ml of saturatedsodium bicarbonate was then added. The resulting mixture was extractedwith DCM, and the organic layer was dried over MgSO₄, filtered, andconcentrated to obtain the title compound (2.5 g). MS m/z: [M+H⁺] calcdfor C₂₆H₃₃N₃O₃, 436.3. found 436.6.

Example 214′-{5-[((S)-2-Acetylsulfanylmethyl-4-methylpentanoylamino)methyl]-2-ethoxy-4-ethylimidazol-1-ylmethyl}biphenyl-2-carboxylicAcid t-Butyl Ester (21a; R^(1a)=t-butyl; R^(5a)=—C(O)CH₃);4′-{5-[((S)-2-Acetylsulfanylmethyl-4-methylpentanoylamino)methyl]-2-ethoxy-4-ethylimidazol-1-ylmethyl}biphenyl-2-carboxylicAcid (21b; R^(1a)═H; R^(5a)=—C(O)CH₃);4′-{2-Ethoxy-4-ethyl-5-[((S)-2-mercaptomethyl-4-methylpentanoylamino)methyl]imidazol-1-ylmethyl}biphenyl-2-carboxylic Acid (21c; R^(1a)═H;R^(5a)═H)

(S)-2-Acetylsulfanylmethyl-4-methylpentanoic acid (1.0 g, 5.1 mmol) wasdissolved in DMF (50 mL, 600 mmol). HATU (1.8 g, 4.8 mmol) and DIPEA(800 μL, 4.6 mmol) were added and the mixture was stirred at roomtemperature for 20 minutes.4′-(5-Aminomethyl-2-ethoxy-4-ethylimidazol-1-ylmethyl)biphenyl-2-carboxylicacid t-butyl ester (2.0 g, 4.6 mmol) in DMF (25 mL, 300 mmol) with DIPEA(800 μL, 4.6 mmol) was added and the mixture was stirred at roomtemperature overnight. The reaction was quenched with water, and themixture was extracted with EtOAc, washed with saturated aqueous NaCl,dried over MgSO₄, filtered, and concentrated to yield the acetylsulfanylester intermediate (21a). This intermediate was taken up in DCM:TFA (4mL each), stirred at room temperature for 4 hours, then concentrated toyield the acetylsulfanyl acid intermediate (21b). This intermediate wasdissolved in 1:1 MeOH:1N NaOH (5 mL each) and stirred at roomtemperature under nitrogen for 1 hour before the reaction was quenchedwith acetic acid and the mixture concentrated. The residue was purifiedby preparative HPLC (10-70% MeCN in water w/0.05% TFA) to obtain thefinal product (20c) (822 mg). MS m/z: [M+H⁺] calcd for C₂₉H₃₇N₃O₄S,524.6. found 524.4. ¹H-NMR (DMSO): 8.33 (1H, s), 7.65 (1H, d), 7.49 (1H,t), 7.38 (1H, t), 7.24 (3H, m), 7.16 (2H, d), 5.05 (2H, s), 4.41 (2H,d), 4.10 (2H, m), 2.41 (3H, m), 2.29 (1H, m), 2.06 (1H, t), 1.20 (8H,m), 0.74 (6H, dd).

Preparation 184′-(5-Aminomethyl-2-propoxy-4-ethylimidazol-1-ylmethyl)-3′-fluorobiphenyl-2-carboxylicacid t-Butyl Ester

4′-(4-Bromo-2-propoxy-5-formylimidazol-1-ylmethyl)-3′-fluorobiphenyl-2-carboxylicacid t-butyl ester (18a): Bromo-2-propoxy-3H-imidazole-4-carbaldehyde(4.5 g, 19.3 mmol), 4′-bromomethyl-3′-fluorobiphenyl-2-carboxylic acidt-butyl ester (7.1 g, 19.5 mmol) and potassium carbonate (8.0 g, 57.9mmol) were dissolved in DMF (100 mL). The solution was stirred at roomtemperature overnight. The reaction was quenched with water, extractedwith 200 mL EtOAc, washed with 4×100 mL saturated aqueous NaCl, driedover MgSO₄, filtered and concentrated in vacuo to yield intermediate(18a) as a colorless oil (10 g), which was used without furtherpurification. Anal. HPLC retention time=5.0 minutes. Gradientconditions: 25% solvent B/75% solvent A to 95% solvent B/5% solvent Aover 6 minutes. MS m/z: [M+H⁺] calcd for C₂₅H₂₆BrFN₂O₄, 517.11. found555.2. [M+K⁺] ¹H-NMR (CDCl₃) 9.55 (1H, s), 7.77 (1H, d), 7.46 (2H, m),7.41 (2H, m), 7.12 (1H, t), 6.99 (2H, d), 5.45 (2H, s), 1.78 (2H, m),1.28 (2H, m), 1.24 (9H, s), 0.98 (3H, s).

4′-(2-Propoxy-5-formyl-4-vinylimidazol-1-ylmethyl)-3′-fluorobiphenyl-2-carboxylicacid t-butyl ester (18b): Intermediate (18a) (10.0 g, 19.3 mmol) wasdissolved in DMF (100 mL). Tetrakis(triphenylphosphine)palladium(0) (400mg, 0.4 mmol) was added, followed by (2-ethenyl)tri-n-butyltin (8.5 mL,29.0 mmol). The reaction vessel was fitted with a reflux condenser andwas heated to 110° C. with stirring for 1 hour, under nitrogen. Themixture was cooled and 200 mL EtOAc was added. The organic layer waswashed with a 20% solution of potassium fluoride (2×50 mL) followed bysaturated aqueous NaCl (100 mL), then dried over MgSO₄, filtered andconcentrated in vacuo. The resulting material was purified by silica gelchromatography (0-80% EtOAc:hexanes) to yield intermediate (18b) as acolorless oil (7.2 g). Anal. HPLC retention time=4.9 minutes. Gradientconditions: 25% solvent B/75% solvent A to 95% solvent B/5% solvent Aover 6 minutes. MS m/z: [M+H⁺] calcd for C₂₇H₂₉FN₂O₄, 465.22. found465.6.

4′-[2-Propoxy-5-(hydroxyiminomethyl)-4-vinylimidazol-1-ylmethyl]-3′-fluorobiphenyl-2-carboxylicacid t-butyl ester (18c): Intermediate (18b) (7.2 g, 15.5 mmol) wasdissolved in pyridine (30 mL). Hydroxylamine hydrochloride (4.0 g, 57.9mmol) was added followed by water (20 mL) and the mixture was stirred at40° C. for 2 hours. The reaction was quenched with water, extracted with200 mL EtOAc, washed with 3×100 mL 1M phosphoric acid, 1×100 mLsaturated sodium bicarbonate solution, and 2×100 mL saturated aqueousNaCl, then dried over MgSO₄, filtered and concentrated in vacuo. Thecrude product was purified by silica gel chromatography (0-80%EtOAc:hexanes) to yield intermediate (18c) as a white solid (7.4 g).Anal. HPLC retention time=4.9 minutes. Gradient conditions: 25% solventB/75% solvent A to 95% solvent B/5% solvent A over 6 minutes. MS m/z:[M+H⁺] calcd for C₂₇H₃₀FN₃O₄, 480.23. found 480.4. ¹H-NMR (DMSO-d₆)10.99 (1H, s), 8.21 (1H, s), 7.67 (1H, d), 7.54 (1H, m), 7.44 (1H, s),7.34 (1H, m), 7.11 (2H, m), 6.81 (2H, m), 5.73 (1H, d), 5.36 (2H, s),5.10 (1H, d), 1.66 (2H, m), 1.13 (9H, s), 0.85 (4H, m).

Intermediate (18c) (7.4 g, 15.0 mmol) was dissolved in EtOAc (200 mL),followed by the addition of sulfuric acid (1.50 mL). 10% Pd/C, Degussatype, wet 50% (0.05:0.45:0.5, palladium:carbon black:water, 16.0 g) wasthen added and the mixture was degassed with nitrogen and then stirredat room temperature under hydrogen for 2 hours. The mixture was thendegassed with nitrogen, the palladium was filtered off under nitrogenand the resulting material was concentrated to obtain the title compoundas a pale yellow oil (6.5 g). Anal. HPLC retention time=3.2 minutes.Gradient conditions: 10% solvent B/90% solvent A to 90% solvent B/10%solvent A over 6 minutes. MS m/z: [M+H⁺] calcd for C₂₇H₃₄FN₃O₃, 468.27.found 468.4. ¹H-NMR (DMSO-d₆) 7.67 (1H, d), 7.54 (1H, t), 7.33 (1H, t)7.10 (1H, d), 7.03 (2H, d), 6.87 (1H, s), 5.08 (1H, s), 4.12 (2H, m),4.00 (2H, s), 3.99 (2H, s), 3.48 (2H, s), 2.32 (2H, m), 1.62 (3H, m),1.14 (9H, s), 0.85 (3H, t).

Example 224′-{5-[((S)-2-Acetylsulfanylmethyl-4-methylpentanoylamino)methyl]-4-ethyl-2-propoxyimidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicAcid t-Butyl Ester (22a; R^(1a)=t-butyl; R^(5a)=—C(O)CH₃);4′-{5-[((S)-2-Acetylsulfanylmethyl-4-methylpentanoylamino)methyl]-4-ethyl-2-propoxyimidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicAcid (22b; R^(1a)═H; R^(5a)=—C(O)CH₃);4′-{4-Ethyl-5-[((S)-2-mercaptomethyl-4-methylpentanoylamino)methyl]-2-propoxyimidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicAcid.C₂HF₃O₂(22c; R^(1a)═H, R^(5a)═H)

HATU (3.1 g, 8.2 mmol) was added to a solution of(S)-2-acetylsulfanylmethyl-4-methylpentanoic acid (1.7 g, 8.2 mmol) inDMF (60 mL), and stirred for 5 minutes at room temperature.4′-(5-Aminomethyl-2-propoxy-4-ethylimidazol-1-ylmethyl)-3′-fluorobiphenyl-2-carboxylicacid t-butyl ester (3.5 g, 7.5 mmol) was added as a DMF solution (5 mL),followed by the addition of DIPEA (2.6 mL, 15.0 mmol). The mixture wasstirred for 15 minutes, then 200 mL EtOAc was added. The organic layerwas washed with 4×100 mL saturated aqueous NaCl, dried over MgSO₄ for 10minutes, filtered and evacuated to dryness in vacuo. The material wasthen concentrated and the resulting crude solid was purified by silicagel chromatography (EtOAc/hexanes, 10-70% EtOAc) to yield theacetylsulfanyl ester intermediate (22a). Anal. HPLC retention time=4.4minutes. Gradient conditions: 10% solvent B/90% solvent A to 90% solventB/10% solvent A over 6 minutes. MS m/z: [M+H⁺] calcd for C₃₆H₄₈FN₃O₅S,654.34. found 654.5.

4N HCl in dioxane (10 mL) was added to intermediate (22a), and themixture was stirred overnight at room temperature. Volatiles wereremoved in vacuo to yield the acetylsulfanyl acid intermediate (22b) asan orange oil, which was used without further purification. Anal. HPLCretention time=3.9 minutes. Gradient conditions: 10% solvent B/90%solvent A to 90% solvent B/10% solvent A over 6 minutes. MS m/z: [M+H⁺]calcd for C₃₂H₄₀FN₃O₅S, 598.28. found 598.5.

10 N NaOH (2.0 mL) was added to a methanolic (50 mL) solution ofintermediate (22b). The solution was stirred at room temperature for 30minutes under nitrogen after which acetic acid (2.0 mL) was added. Thesolution was concentrated and purified by preparative HPLC (reversephase): gradient of 20-65% (over 60 minutes); flow rate 15 mL/min;detection at 280 nm. Pure fractions were combined and lyophilized in50/50 water/MeCN to give the final product (22c) as a white solid TFAsalt (1.4 g). Anal. HPLC retention time=3.9 minutes. Gradientconditions: 10% solvent B/90% solvent A to 90% solvent B/10% solvent Aover 6 minutes. MS m/z: [M+H⁺] calcd for C₃₀H₃₈FN₃O₄S, 556.26. found556.2. ¹H-NMR (d₄-MeOH) 8.57 (1H, t), 7.86 (1H, d), 7.55 (1H, t), 7.46(1H, t) 7.32 (1H, d), 7.22 (2H, t), 7.12 (2H, m), 5.32 (1H, s), 4.42(2H, m), 4.3-4.4 (1H, m), 2.73 (2H, m), 2.55 (2H, m), 2.42 (1H, m), 1.80(2H, m), 1.48 (2H, m), 1.26 (2H, m), 0.94 (3H, t), 0.86 (3H, m).

Example 234′-{5-[((S)-2-Acetylsulfanyl-4-methylpentanoylamino)methyl]-4-ethyl-2-propoxyimidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicAcid t-Butyl Ester (23a; R^(1a)=t-butyl; R^(5a)=—C(O)CH₃);4′-{5-[((S)-2-Acetylsulfanyl-4-methylpentanoylamino)methyl]-4-ethyl-2-propoxyimidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicAcid (23b; R^(1a)═H, R^(5a)=—C(O)CH₃);4′-{4-Ethyl-5-[((S)-2-mercapto-4-methylpentanoylamino)methyl]-2-propoxyimidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicAcid.C₂HF₃O₂ (23c; R^(1a)═H; R^(5a)═H)

HATU (4.3 g, 11.3 mmol) was added to a solution of(S)-2-acetylsulfanyl-4-methylpentanoic acid (2.2 g, 11.3 mmol) in DMF(80 mL), and stirred for 5 minutes at room temperature.4′-(5-Aminomethyl-2-propoxy-4-ethylimidazol-1-ylmethyl)-3′-fluorobiphenyl-2-carboxylicacid t-butyl ester (4.8 g, 10.3 mmol) was added as a DMF solution (5 mL)followed by DIPEA (3.6 mL, 20.5 mmol). The mixture was stirred for 15minutes, then 200 mL EtOAc was added. The organic layer was washed with4×100 mL saturated aqueous NaCl, dried over MgSO₄ for 10 minutes,filtered and evacuated to dryness. The mixture was concentrated and theresulting crude solid was purified by flash chromatography(EtOAc/hexanes, 10-70% EtOAc) to yield the acetylsulfanyl esterintermediate (23a). Anal. HPLC retention time=3.4 minutes. Gradientconditions: 25% solvent B/75% solvent A to 95% solvent B/5% solvent Aover 6 minutes. MS m/z: [M+H⁺] calcd for C₃₅H₄₆FN₃O₅S, 640.32. found640.0.

4N HCl in dioxane (10 mL) was added to intermediate (23a), and themixture was stirred overnight at room temperature. Volatiles wereremoved in vacuo to yield the acetylsulfanyl acid intermediate (23b) asan orange oil, which was used without further purification. Anal. HPLCretention time=2.9 minutes. Gradient conditions: 25% solvent B/75%solvent A to 95% solvent B/5% solvent A over 6 minutes. MS m/z: [M+H⁺]calcd for C₃₁H₃₈FN₃O₅S, 584.26. found 584.0.

10 N NaOH (2.0 mL) was added to a methanolic (50 mL) solution ofintermediate (23b). The solution was stirred at room temperature for 30minutes under nitrogen after which acetic acid (2.0 mL) was added. Thesolution was concentrated and purified by preparative HPLC (reversephase): gradient of 20-65% (over 60 minutes); flow rate 15 mL/min;detection at 280 nm. Pure fractions were combined and lyophilized in50/50 water/MeCN to give the final product (23c) as a white solid TFAsalt (1.0 g). Anal. HPLC retention time=3.9 minutes. Gradientconditions: 10% solvent B/90% solvent A to 90% solvent B/10% solvent Aover 6 minutes. MS m/z: [M+H⁺] calcd for C₂₉H₃₆FN₃O₄S, 542.25. found542.6. ¹H-NMR (d₄-MeOH) 8.53 (1H, t), 7.86 (1H, d), 7.56 (1H, t), 7.46(1H, t) 7.32 (1H, d), 7.20 (2H, t), 7.12 (2H, m), 5.29 (1H, s), 4.42(2H, m), 4.3-4.4 (1H, m), 2.73 (2H, m), 2.55 (2H, m), 1.80 (2H, m), 1.48(2H, m), 1.26 (2H, m), 0.94 (3H, t), 0.86 (3H, m).

Example 24

Following the procedures described in the examples above, andsubstituting the appropriate starting materials and reagents, compounds24-1 to 24-3, having the following formula, were also prepared:

Ex. R³ R⁵ 24-1 —O—(CH₂)₂CH₃ —SH 24-2 —O—CH₂CH₃ —CH₂SH 24-3 —O—(CH₂)₂CH₃—CH₂SH

(24-1)2,3-difluoro-4-{5-[((S)-2-mercapto-4-methylpentanoylamino)methyl]-2-propoxyimidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₁H₂₇F₂N₃O₄S, 456.17. found 456.2.

(24-2)4-{2-ethoxy-5-[((S)-2-mercaptomethyl-4-methylpentanoylamino)methyl]-imidazol-1-ylmethyl}-2,3-difluorobenzoicacid. MS m/z: [M+H⁺] calcd for C₂₁H₂₇F₂N₃O₄S, 456.17. found 456.2.

(24-3)2,3-difluoro-4-{5-[((S)-2-mercaptomethyl-4-methylpentanoylamino)methyl]-2-propoxyimidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₂H₂₉F₂N₃O₄S, 470.18. found 470.4.

Example 25

Following the procedures described in the examples above, andsubstituting the appropriate starting materials and reagents, compounds25-1 to 25-70 having the following formula where one or two R groups areoptionally present, were also prepared.

Ex. R R¹ R² R³ R⁵ R⁶ 25-1 — —COOH H —O—(CH₂)₂CH₃ —CH₂SH —CH₂—CH(CH₃)₂25-2 — —COOH H —O—CH₂CH₃ —CH₂SH —CH₂—CH(CH₃)₂ 25-3 — —COOH —CH₂CH₃—O—(CH₂)₂CH₃ —CH₂SH —CH₂—CH(CH₃)₂ 25-4 — —COOH —CH₂CH₃ —O—(CH₂)₂CH₃ —SH—CH₂—CH(CH₃)₂ 25-5 — —COOH —CH₂CH₃ O—CH₂CH₃ —SH —CH₂—CH(CH₃)₂ 25-6 ——SO₂—NH—C(O)CH₃ H —O—(CH₂)₂CH₃ —CH₂SH —CH₂—CH(CH₃)₂ 25-7 ——SO₂—NH—C(O)CH₃ —CH₂CH₃ —O—(CH₂)₂CH₃ —CH₂SH —CH₂—CH(CH₃)₂ 25-8 ——SO₂—NHC(O)—CH₂CH₃ H —O—(CH₂)₂CH₃ —CH₂SH —CH₂—CH(CH₃)₂ 25-9 2′-F —COOH—CH₂CH₃ —O—(CH₂)₂CH₃ —SH —CH₂—CH(CH₃)₂ 25-10 2′-F —COOH —CH₂CH₃—O—(CH₂)₂CH₃ —CH₂SH —CH₂—CH(CH₃)₂ 25-11 2′-F —COOH —CH₂CH₃ —O—(CH₂)₂CH₃—SH —CH₂—CH(CH₃)₂ 25-12 2′-F —COOH —CH₂CH₃ —O—(CH₂)₂CH₃ —CH₂SH—CH₂—CH(CH₃)₂ 25-13 2′-Cl —COOH —CH₂CH₃ —O—(CH₂)₂CH₃ —SH —CH₂—CH(CH₃)₂25-14 3′-Cl —COOH —CH₂CH₃ —O—(CH₂)₂CH₃ —SH —CH₂—CH(CH₃)₂ 25-15 — —COOH—CH₂CH₃ —O—CH₂CH₃ —CH₂—SC(O)CH₃ —CH₂—CH(CH₃)₂ 25-16 3′-F —COOH —CH₂CH₃—O—CH₂CH₃ —SC(O)—CH₃ —CH₂—CH(CH₃)₂ 25-17 2′-F —COOH —CH₂CH₃ —O—CH₂CH₃—CH₂SH —CH₂—CH(CH₃)₂ 25-18 2′-F —COOH —CH₂CH₃ —O—CH₂CH₃ —SH—CH₂—CH(CH₃)₂ 25-19 3′-F —COOH —CH₂CH₃ —O—(CH₂)₂CH₃ —SC(O)—CH₃—CH₂—CH(CH₃)₂ 25-20 3′-F —COOH —CH₂CH₃ —OCH₃ —CH₂SH —CH₂—CH(CH₃)₂ 25-213′-F —COOH —CH₂CH₃ —OCH₃ —SH —CH₂—CH(CH₃)₂ 25-22 3′-F —COOH —CH₂CH₃—O—CH₂CH₃ —SC(O)—CH₃ —CH₂—CH(CH₃)₂ 25-23 3′-F —COOH —CH₂CH₃ —O—CH₂CH₃—CH₂S—C(O)CH₃ —CH₂—CH(CH₃)₂ 25-24 — —COOH cyclopropyl —O—(CH₂)₂CH₃ —SH—CH₂—CH(CH₃)₂ 25-25 — —COOH cyclopropyl —O—(CH₂)₂CH₃ —CH₂SH—CH₂—CH(CH₃)₂ 25-26 — —COOH cyclopropyl —O—CH₂CH₃ —CH₂SH —CH₂—CH(CH₃)₂25-27 3′-F —COOH —CH₂CH₃ —O—CH₂CH₃ —SH —CH₂-cyclopropyl 25-28 3′-F —COOHcyclopropyl —O—(CH₂)₂CH₃ —SH —CH₂—CH(CH₃)₂ 25-29 3′-F —NHSO₂CF₃ —CH₂CH₃—O—CH₂CH₃ —SH —CH₂—CH(CH₃)₂ 25-30 — —SO₂NH—C(O)CH₃ —CH₂CH₃ —O—CH₂CH₃ —SH—CH₂—CH(CH₃)₂ 25-31 3-F —SO₂NH—C(O)CH₃ —CH₂CH₃ —OCH₃ —CH₂SH—CH₂—CH(CH₃)₂ 25-32 3′-F —COOH —CH₂CH₃ —O—CH₂CH₃ —SH —(CH₂)₂CH₃ 25-333′-F —COOH —CH₂CH₃ —O—CH₂CH₃ —SH —CH₂—CH(CH₃)₂ 25-34 3′-F —COOH —CH₂CH₃—O—CH₂CH₃ —SH —CH₂C(CH₃)₃ 25-35 3′-F —COOH —CH₂CH₃ —O—CH₂CH₃—SC(O)-phenyl —CH₂—CH(CH₃)₂ 25-36 3′-F —COOH —CH₂CH₃ —O—CH₂CH₃—SC(O)—CH₂-morpholine —CH₂—CH(CH₃)₂ 25-37 3′-F —COOH —CH₂CH₃ —O—CH₂CH₃—SC(O)—(CH₂)₂-morpholine —CH₂—CH(CH₃)₂ 25-38 — —COOH —CH₃ —O—CH₂CH₃ —SH—CH₂—CH(CH₃)₂ 25-39 — —COOH —CH₃ —O—CH₂CH₃ —CH₂SH —CH₂—CH(CH₃)₂ 25-40 ——COOH —CH₂CH₃ —O—CH₂CH₃ —SH —CH₂CH₃ 25-41 — —COOH —CH₂CH₃ —O—CH₂CH₃ —SH—CH(CH₃)—CH₂CH₃ 25-42 3′-F —COOH —CH₂CH₃ —O—CH₂CH₃ —SC(O)—CH₂CH₃—CH₂—CH(CH₃)₂ 25-43 3′-F —COOH —CH₃ —O—CH₂CH₃ —SH —CH₂—CH(CH₃)₂ 25-443′-F —COOH —CH₃ —O—CH₂CH₃ —CH₂SH —CH₂—CH(CH₃)₂ 25-45 3′-F —COOH —CH₂CH₃—O—CH₂CH₃ —SH —CH₂-cyclopropyl 25-46 — —COOH cyclopropyl —O—CH₂CH₃ —SH—CH₂—CH(CH₃)₂ 25-47 3′-F —COOH —O—CH₃ —(CH₂)₃CH₃ —SH —CH₂—CH(CH₃)₂ 25-483′-F —COOH —O—CH₃ —(CH₂)₃CH —CH₂SH —CH₂—CH(CH₃)₂ 25-49 3′-F —COOH —O—CH₃—(CH₂)₃CH —SH —CH(CH₃)—CH₂CH₃ 25-50 2′-F —COOH —Cl —(CH₂)₃CH₃ —CH₂SH—CH₂—CH(CH₃)₂ 25-51 3′-F —COOH cyclopropyl —O—CH₂CH₃ —SH —CH₂—CH(CH₃)₂25-52 3′-F —COOH —CH₂CH₃ —O—CH₂CH₃ —CH₂—N(OH)—CHO —CH₂—CH(CH₃)₂ 25-533′-F —COOH —CH₂CH₃ —O—CH₂CH₃ —CH₂—N(OH)—CHO benzyl 25-54 3′-F —COOH —Cl—(CH₂)₃CH₃ —SH —CH₂—CH(CH₃)₂ 25-55 3′-F —COOH —Cl —(CH₂)₃CH₃ —CH₂SH—CH₂—CH(CH₃)₂ 25-56 3′-F —COOH —CH₂OH —O—CH₂CH₃ —SH —CH₂—CH(CH₃)₂ 25-573′-F —COOH —CH₂OH —O—CH₂CH₃ —CH₂SH —CH₂—CH(CH₃)₂ 25-58 — tetrazol-5-yl—CH₂CH₃ —O—CH₂CH₃ —SH —CH₂—CH(CH₃)₂ 25-59 3′-F —COOH —C(CH₃)₂—OH—(CH₂)₂CH₃ —SH —CH₂—CH(CH₃)₂ 25-60 3′-F —COOH —C(CH₃)₂—OH —(CH₂)₂CH₃—CH₂SH —CH₂—CH(CH₃)₂ 25-61 3′-F —COOH —CH₂CH₃ —O—CH₂CH₃ —SH—(CH₂)₂-phenyl 25-62 3′-F —COOH —CH₂CH₃ —O—CH₂CH₃ —SH —CH(CH₃)—CH₂CH₃25-63 3′-F —COOH —CH₂CH₃ —O—CH₂CH₃ —SH phenyl 25-64 3′-F —COOH —CH₂CH₃—O—CH₂CH₃ —SH 2-chlorophenyl 25-65 3′-F —COOH —CH₂CH₃ —O—CH₂CH₃ —SH—CH₂-cyclohexyl 25-66 3′-F —COOH —CH₂CH₃ —O—CH₂CH₃ —SH cyclopropyl 25-673′-F —COOH Cl —O—CH₂CH₃ —SC(O)CH₃ —CH₂—CH(CH₃)₂ 25-68 3′-F —COOH —CH₂CH₃—O—CH₂CH₃ —C(O)—NH(OH) benzyl 25-69 3′-F —COOH —CH₂CH₃ —O—CH₂CH₃—C(O)—NH(OH) —CH₂—CH(CH₃)₂ 25-70 3′-F —COOH —CH₂CH₃ —O—CH₂CH₃ —SH—CH₂-cyclobutyl

(25-1)4′-{5-[((S)-2-mercaptomethyl-4-methylpentanoylamino)methyl]-2-propoxyimidazol-1-ylmethyl}-biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₂₈H₃₅N₃O₄S, 510.24. found 510.5.

(25-2)4′-{2-ethoxy-5-[((S)-2-mercaptomethyl-4-methylpentanoylamino)methyl]-imidazol-1-ylmethyl}-biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₂₇H₃₃N₃O₄S, 496.22. found 496.3.

(25-3)4′-{4-ethyl-5-[((S)-2-mercaptomethyl-4-methylpentanoylamino)methyl]-2-propoxyimidazol-1-ylmethyl}-biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₀H₃₉N₃O₄S, 538.27. found 538.5.

(25-4)4′-{4-ethyl-5-[((S)-2-mercapto-4-methylpentanoylamino)methyl]-2-propoxyimidazol-1-ylmethyl}-biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₂₉H₃₇N₃O₄S, 524.25. found 524.6.

(25-5)4′-{2-ethoxy-4-ethyl-5-[((S)-2-mercapto-4-methylpentanoylamino)methyl]-imidazol-1-ylmethyl}-biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₂₈H₃₅N₃O₄S, 510.24. found 510.5.

(25-6) (S)-2-mercaptomethyl-4-methylpentanoic acid[3-(2′-acetylsulfamoyl-biphenyl-4-ylmethyl)-2-propoxy-3H-imidazol-4-ylmethyl]amide.MS m/z: [M+H⁺] calcd for C₂₉H₃₈N₄O₅S₂, 587.23. found 587.5.

(25-7) (S)-2-mercaptomethyl-4-methylpentanoic acid[3-(2′-acetylsulfamoyl-biphenyl-4-ylmethyl)-5-ethyl-2-propoxy-3H-imidazol-4-ylmethyl]amide.MS m/z: [M+H⁺] calcd for C₃₁H₄₂N₄O₅S₂, 615.26. found 615.4.

(25-8)(S)—N-((1-((2′-(N-(ethylcarbamoyl)sulfamoyl)biphenyl-4-yl)methyl)-2-propoxy-1H-imidazol-5-yl)methyl)-2-(mercaptomethyl)-4-methylpentanamide.MS m/z: [M+H⁺]calcd for C₃₀H₄₁N₅O₅S₂, 616.26. found 616.4.

(25-9)4′-{4-ethyl-5-[((S)-2-mercapto-4-methylpentanoylamino)methyl]-2-propoxyimidazol-1-ylmethyl}-2′-fluorobiphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₂₉H₃₆FN₃O₄S, 542.24. found 542.6.

(25-10)4′-{4-ethyl-5-[((S)-2-mercaptomethyl-4-methylpentanoylamino)methyl]-2-propoxyimidazol-1-ylmethyl}-2′-fluorobiphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₀H₃₈FN₃O₄S, 556.26. found 556.2.

(25-11)4′-{4-ethyl-5-[((R)-2-mercapto-4-methylpentanoylamino)methyl]-2-propoxyimidazol-1-ylmethyl}-2′-fluorobiphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₂₉H₃₆FN₃O₄S, 542.24. found 542.6.

(25-12)4′-{4-ethyl-5-[((R)-2-mercaptomethyl-4-methylpentanoylamino)methyl]-2-propoxyimidazol-1-ylmethyl}-2′-fluorobiphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₀H₃₈FN₃O₄S, 556.26. found 556.2.

(25-13)2′-chloro-4′-{4-ethyl-5-[((S)-2-mercapto-4-methylpentanoylamino)methyl]-2-propoxyimidazol-1-ylmethyl}-biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₂₉H₃₆ClN₃O₄S, 558.21. found 558.2.

(25-14)3′-chloro-4′-{4-ethyl-5-[((S)-2-mercapto-4-methylpentanoylamino)methyl]-2-propoxyimidazol-1-ylmethyl}-biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₂₉H₃₆ClN₃O₄S, 558.21. found 558.4.

(25-15)4′-{5-[((S)-2-acetylsulfanylmethyl-4-methylpentanoylamino)methyl]-2-ethoxy-4-ethyl-imidazol-1-ylmethyl}-biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₁H₃₉N₃O₅S, 566.26. found 566.6.

(25-16)4′-{5-[((S)-2-acetylsulfanyl-4-methylpentanoylamino)methyl]-2-ethoxy-4-ethyl-imidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₀H₃₆FN₃O₅S, 570.24. found 570.4.

(25-17)4′-{2-ethoxy-4-ethyl-5-[((S)-2-mercaptomethyl-4-methylpentanoylamino)methyl]-imidazol-1-ylmethyl}-2′-fluorobiphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₂₉H₃₆FN₃O₄S, 542.24. found 542.6.

(25-18)4′-{2-ethoxy-4-ethyl-5-[((S)-2-mercapto-4-methylpentanoylamino)methyl]-imidazol-1-ylmethyl}-2′-fluorobiphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₂₈H₃₄FN₃O₄S, 528.23. found 528.4.

(25-19)4′-{5-[((S)-2-acetylsulfanyl-4-methylpentanoylamino)methyl]-4-ethyl-2-propoxyimidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₁H₃₈FN₃O₅S, 584.25. found 584.0.

(25-20)4′-{4-ethyl-5-[((S)-2-mercaptomethyl-4-methylpentanoylamino)methyl]-2-methoxyimidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₂₈H₃₄FN₃O₄S, 528.23. found 528.4.

(25-21)4′-{4-ethyl-5-[((S)-2-mercapto-4-methylpentanoylamino)methyl]-2-methoxyimidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₂₇H₃₂FN₃O₄S, 514.21. found 514.6.

(25-22)4′-{5-[(2-acetylsulfanyl-4-methylpentanoylamino)methyl]-2-ethoxy-4-ethylimidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₀H₃₆FN₃O₅S, 570.24. found 570.4.

(25-23)4′-{5-[((S)-2-acetylsulfanylmethyl-4-methylpentanoylamino)methyl]-2-ethoxy-4-ethylimidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₁H₃₈FN₃O₅S, 584.25. found 584.5.

(25-24)4′-{4-cyclopropyl-5-[((S)-2-mercapto-4-methylpentanoylamino)methyl]-2-propoxyimidazol-1-ylmethyl}-biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₀H₃₇N₃O₄S, 536.25. found 536.4.

(25-25)4′-{4-cyclopropyl-5-[((S)-2-mercaptomethyl-4-methylpentanoylamino)methyl]-2-propoxyimidazol-1-ylmethyl}-biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₁H₃₉N₃O₄S, 550.27. found 550.4.

(25-26)4′-{4-cyclopropyl-2-ethoxy-5-[((S)-2-mercaptomethyl-4-methylpentanoyl-amino)methyl]-imidazol-1-ylmethyl}-biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₀H₃₇N₃O₄S, 536.25. found 536.4.

(25-27)4′-{5-[((S)-3-cyclopropyl-2-mercapto-propionylamino)methyl]-2-ethoxy-4-ethyl-imidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₂₈H₃₂FN₃O₄S, 526.21. found 526.4.

(25-28)4′-{4-cyclopropyl-5-[((S)-2-mercapto-4-methylpentanoylamino)methyl]-2-propoxyimidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₀H₃₆FN₃O₄S, 554.24. found 554.2.

(25-29) (S)-2-mercapto-4-methylpentanoic acid[2-ethoxy-5-ethyl-3-(3-fluoro-2′-trifluoromethanesulfonylamino-biphenyl-4-ylmethyl)-3H-imidazol-4-ylmethyl]amide.MS m/z: [M+H⁺] calcd for C₂₈H₃₄F₄N₄O₄S₂, 631.20. found 631.4.

(25-30) (S)-2-mercapto-4-methylpentanoic acid[3-(2′-acetylsulfamoyl-biphenyl-4-ylmethyl)-2-ethoxy-5-ethyl-3H-imidazol-4-ylmethyl]amide.MS m/z: [M+H⁺] calcd for C₂₉H₃₈N₄O₅S₂, 587.23. found 587.2.

(25-31) (S)-2-mercaptomethyl-4-methylpentanoic acid[3-(2′-acetylsulfamoyl-3-fluorobiphenyl-4-ylmethyl)-5-ethyl-2-methoxy-3H-imidazol-4-ylmethyl]amide.MS m/z: [M+H⁺] calcd for C₂₉H₃₇FN₄O₅S₂, 605.22. found 605.4.

(25-32)4′-{2-ethoxy-4-ethyl-5-[((S)-2-mercaptopentanoylamino)methyl]-imidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₂₇H₃₂FN₃O₄S, 514.21. found 514.4.

(25-33)4′-{2-ethoxy-4-ethyl-5-[(2-mercapto-4-methylpentanoylamino)methyl]-imidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₂₈H₃₄FN₃O₄S, 528.23. found 529.0.

(25-34)4′-{2-ethoxy-4-ethyl-5-[((S)-2-mercapto-4,4-dimethylpentanoylamino)methyl]-imidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₂₉H₃₆FN₃O₄S, 542.24. found 542.4.

(25-35)4′-{5-[((S)-2-benzoylsulfanyl-4-methylpentanoylamino)methyl]-2-ethoxy-4-ethylimidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₅H₃₈FN₃O₅S, 632.25. found 632.4.

(25-36)4′-(2-ethoxy-4-ethyl-5-{[(S)-4-methyl-2-(2-morpholin-4-yl-acetylsulfanyl)-pentanoylamino]-methyl}-imidazol-1-ylmethyl)-3′-fluorobiphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₄H₄₃FN₄O₆S, 655.29. found 655.6.

(25-37)4′-(2-ethoxy-4-ethyl-5-{[(S)-4-methyl-2-(3-morpholin-4-yl-propionylsulfanyl)-pentanoylamino]methyl}-imidazol-1-ylmethyl)-3′-fluorobiphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₅H₄₅FN₄O₆S, 669.30. found 669.5.

(25-38)4′-{2-ethoxy-5-[((S)-2-mercapto-4-methylpentanoylamino)methyl]-4-methyl-imidazol-1-ylmethyl}-biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₂₇H₃₃N₃O₄S, 496.22. found 496.6.

(25-39)4′-{2-ethoxy-5-[((S)-2-mercaptomethyl-4-methylpentanoylamino)methyl]-4-methyl-imidazol-1-ylmethyl}-biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₂₈H₃₅N₃O₄S, 510.24. found 510.6.

(25-40)4′-{2-ethoxy-4-ethyl-5-[((S)-2-mercaptobutyrylamino)methyl]-imidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₂₆H₃₀FN₃O₄S, 500.19. found 500.4.

(25-41)4′-{2-ethoxy-4-ethyl-5-[((2S,3S)-2-mercapto-3-methylpentanoylamino)methyl]-imidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₂₈H₃₄FN₃O₄S, 528.23. found 528.4.

(25-42)4′-{2-ethoxy-4-ethyl-5-[((S)-4-methyl-2-propionylsulfanylpentanoylamino)-methyl]imidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₁H₃₈FN₃O₅S, 584.25. found 584.2.

(25-43)4′-{2-ethoxy-5-[((S)-2-mercapto-4-methylpentanoylamino)methyl]-4-methyl-imidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₂₇H₃₂FN₃O₄S, 514.21. found 514.6.

(25-44)4′-{2-ethoxy-5-[((S)-2-mercaptomethyl-4-methylpentanoylamino)methyl]-4-methyl-imidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₂₈H₃₄FN₃O₄S, 528.23. found 528.2.

(25-45)4′-{5-[((S)-3-cyclopentyl-2-mercaptopropionylamino)methyl]-2-ethoxy-4-ethyl-imidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₀H₃₆FN₃O₄S, 554.24. found 554.4.

(25-46)4′-{4-cyclopropyl-2-ethoxy-5-[((S)-2-mercapto-4-methylpentanoylamino)-methyl]imidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₂₉H₃₅N₃O₄S, 522.24. found 522.4.

(25-47)4′-{2-butyl-5-[((S)-2-mercapto-4-methylpentanoylamino)methyl]-4-methoxy-imidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₂₉H₃₆FN₃O₄S, 542.24. found 542.2.

(25-48)4′-{2-butyl-5-[((S)-2-mercaptomethyl-4-methylpentanoylamino)methyl]-4-methoxyimidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₀H₃₈FN₃O₄S, 556.26. found 556.2.

(25-49)4′-{2-butyl-5-[((2S,3S)-2-mercapto-3-methylpentanoylamino)methyl]-4-methoxyimidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₂₉H₃₆FN₃O₄S, 542.24. found 542.2.

(25-50)4′-{2-butyl-4-chloro-5-[((S)-2-mercaptomethyl-4-methylpentanoylamino)-methyl]imidazol-1-ylmethyl}-2′-fluorobiphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₂₉H₃₅ClFN₃O₃S, 560.21. found 560.2.

(25-51)4′-{4-cyclopropyl-2-ethoxy-5-[((S)-2-mercapto-4-methylpentanoylamino)-methyl]imidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₂₉H₃₄FN₃O₄S, 540.23. found 540.4.

(25-52)4′-[2-ethoxy-4-ethyl-5-({2-[(formylhydroxyamino)methyl]-4-methylpentanoyl-amino}methyl)imidazol-1-ylmethyl]-3′-fluorobiphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₀H₃₇FN₄O₆, 569.27. found 569.6.

(25-53)4′-(5-{[2-benzyl-3-(formylhydroxyamino)propionylamino]methyl}-2-ethoxy-4-ethyl-imidazol-1-ylmethyl)-3′-fluorobiphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₃H₃₅FN₄O₆, 603.25. found 603.4.

(25-54)4′-{2-butyl-4-chloro-5-[((S)-2-mercapto-4-methylpentanoylamino)methyl]-imidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₂₈H₃₃ClFN₃O₃S, 546.19. found 546.6.

(25-55)4′-{2-butyl-4-chloro-5-[((S)-2-mercaptomethyl-4-methylpentanoylamino)-methyl]imidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₂₉H₃₅ClFN₃O₃S, 560.21. found 560.2.

(25-56)4′-{2-ethoxy-4-hydroxymethyl-5-[((S)-2-mercapto-4-methylpentanoylamino)-methyl]-imidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₂₇H₃₂FN₃O₅S, 530.20. found 530.4.

(25-57)4′-{2-ethoxy-4-hydroxymethyl-5-[((S)-2-mercaptomethyl-4-methylpentanoyl-amino)-methyl]-imidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₂₈H₃₄FN₃O₅S, 544.22. found 544.4.

(25-58) (S)-2-mercapto-4-methyl-pentanoic acid{2-ethoxy-5-ethyl-3-[2′-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-3H-imidazol-4-ylmethyl}amide.MS m/z: [M+H⁺] calcd for C₂₈H₃₅N₇O₂S, 534.26. found 534.4.

(25-59)3′-fluoro-{4′-4-(1-hydroxy-1-methylethyl)-5-[((S)-2-mercapto-4-methyl-pentanoylamino)methyl]-2-propylimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₀H₃₈FN₃O₄S, 556.26. found 556.4.

(25-60)3′-fluoro-4′-{4-(1-hydroxy-1-methylethyl)-5-[((S)-2-mercaptomethyl-4-methylpentanoylamino)methyl]-2-propylimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₁H₄₀FN₃O₄S, 570.27. found 570.4.

(25-61)4′-{2-ethoxy-4-ethyl-5-[(2-mercapto-4-phenylbutyrylamino)methyl]imidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₂H₃₄FN₃O₄S, 576.23. found 576.4.

(25-62)4′-{2-ethoxy-4-ethyl-5-[((2S,3R)-2-mercapto-3-methylpentanoylamino)methyl]-imidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₂₈H₃₄FN₃O₄S, 528.23. found 528.4.

(25-63)4′-{2-ethoxy-4-ethyl-5-[(2-mercapto-2-phenylacetylamino)methyl]imidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₀H₃₀FN₃O₄S, 548.19. found 548.4.

(25-64)4′-(5-{[2-(2-chloro-phenyl)-2-mercaptoacetylamino]methyl}-2-ethoxy-4-ethylimidazol-1-ylmethyl)-3′-fluorobiphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₀H₂₉ClFN₃O₄S, 582.16. found 582.2.

(25-65)4′-{5-[((S)-3-cyclohexyl-2-mercaptopropionylamino)methyl]-2-ethoxy-4-ethylimidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₁H₃₈FN₃O₄S, 568.26. found 568.4.

(25-66)4′-{5-[((S)-2-cyclopentyl-2-mercaptoacetylamino)methyl]-2-ethoxy-4-ethylimidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicacid. MS m/z: calcd for C₂₉H₃₄FN₃O₄S, 540.23. found 540.4.

(25-67)4′-{5-[((S)-2-acetylsulfanyl-4-methylpentanoylamino)methyl]-4-chloro-2-ethoxyimidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₂₈H₃₁ClFN₃O₅S, 576.17. found 576.4.

(25-68)4′-{2-ethoxy-4-ethyl-5-[(2-hydroxycarbamoyl-3-phenylpropionylamino)-methyl]imidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₂H₃₃FN₄O₆, 589.24. found 589.4.

(25-69)4′-{2-ethoxy-4-ethyl-5-[(2-hydroxycarbamoyl-4-methylpentanoylamino)-methyl]imidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₂₉H₃₅FN₄O₆, 555.25. found 555.2.

(25-70)4′-{5-[((S)-3-cyclobutyl-2-mercaptopropionylamino)methyl]-2-ethoxy-4-ethylimidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₂₉H₃₄FN₃O₄S, 540.23. found 540.5.

Following the procedures described in the examples above, andsubstituting the appropriate starting materials and reagents, compounds25-71- to 25-95 can also readily be prepared.

Ex. R R¹ R² R³ R⁵ R⁶ 25-71 3′-F —COOH Cl —(CH₂)₂CH₃ —SH —CH₂—CH(CH₃)₂25-72 3′-F —COOH Cl —(CH₂)₂CH₃ —CH₂SH —CH₂—CH(CH₃)₂ 25-73 2′,5′-diF—COOH —CH₂CH₃ —O—CH₂CH₃ —SH —CH₂—CH(CH₃)₂ 25-74 2′,5′-diF —COOH —CH₂CH₃—O—CH₂CH₃ —CH₂SH —CH₂—CH(CH₃)₂ 25-75 3′-F —COOH —CH₂F —O—CH₂CH₃ —SH—CH₂—CH(CH₃)₂ 25-76 3′-F —COOH —CH₂F —O—CH₂CH₃ —CH₂SH —CH₂—CH(CH₃)₂25-77 — —COOH —CF₃ —O—CH₂CH₃ —SH —CH₂—CH(CH₃)₂ 25-78 — —COOH Br—O—CH₂CH₃ —SH —CH₂—CH(CH₃)₂ 25-79 — tetrazol-5-yl —CH₂CH₃ —O—CH₂CH₃—SC(O)CH₃ —CH₂—CH(CH₃)₂ 25-80 3′-F tetrazol-5-yl Cl —O—CH₂CH₃ —SH—CH₂—CH(CH₃)₂ 25-81 3′-F tetrazol-5-yl cyclo- —O—CH₂CH₃ —SH—CH₂—CH(CH₃)₂ propyl 25-82 3′-F —COOH Cl —OCH₃ —SH —CH₂—CH(CH₃)₂ 25-833′-F —COOH Cl —O—(CH₂)₂CH₃ —SH —CH₂—CH(CH₃)₂ 25-84 3′-F —COOH Cl —OCH₃—CH₂SH —CH₂—CH(CH₃)₂ 25-85 3′-F —COOH Cl —O—(CH₂)₂CH₃ —CH₂SH—CH₂—CH(CH₃)₂ 25-86 3′-F —C(O)OCH₃ —CH₂CH₃ —O—CH₂CH₃ —SC(O)CH₃—CH₂—CH(CH₃)₂ 25-87 3′-F —C(O)OCH₃ —CH₂CH₃ —O—CH₂CH₃ —SH —CH₂—CH(CH₃)₂25-88 3′-F —C(O)—NHSO₂CF₃ —CH₂CH₃ —O—CH₂CH₃ —SH —CH₂—CH(CH₃)₂ 25-89 3′-F—COOH —CH₂CH₃ —O—CH₂CH₃ —SH benzyl 25-90 3′-F —COOH —CH₂CH₃ —O—CH₂CH₃—SH —CH₂—CF₃ 25-91 3′-F —COOH —CH₂CH₃ —O—CH₂CH₃ —SH —(CH₂)₂—CF₃ 25-923′-F —COOH —CH₂CH₃ —O—CH₂CH₃ —SH 2-fluorophenyl 25-93 3′-F —COOH —CH₂CH₃—O—CH₂CH₃ —SH 4-chlorobenzyl 25-94 3′-F —COOH —CH₂CH₃ —O—CH₂CH₃ —SH2-fluorobenzyl 25-95 3′-F —COOH —CH₂CH₃ —O—CH₂CH₃ —SH 3-fluorobenzyl

(25-71)4′-{4-chloro-5-[((S)-2-mercapto-4-methylpentanoylamino)-methyl]-2-propyl-imidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicacid.

(25-72)4′-{4-chloro-5-[((S)-2-mercaptomethyl-4-methylpentanoylamino)methyl]-2-propylimidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicacid.

(25-73)4′-{2-ethoxy-4-ethyl-5-[((S)-2-mercapto-4-methylpentanoylamino)methyl]-imidazol-1-ylmethyl}-2′,5′-difluorobiphenyl-2-carboxylicacid.

(25-74)4′-{2-ethoxy-4-ethyl-5-[((S)-2-mercaptomethyl-4-methylpentanoylamino)-methyl]imidazol-1-ylmethyl}-2′,5′-difluorobiphenyl-2-carboxylicacid.

(25-75)4′-{2-ethoxy-4-fluoromethyl-5-[((S)-2-mercapto-4-methylpentanoylamino)-methyl]imidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicacid.

(25-76)4′-{2-ethoxy-4-fluoromethyl-5-[((S)-2-mercaptomethyl-4-methylpentanoyl-amino)methyl]imidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicacid.

(25-77)4′-{2-ethoxy-5-[((S)-2-mercapto-4-methylpentanoylamino)methyl]-4-trifluoro-methylimidazol-1-ylmethyl}biphenyl-2-carboxylicacid.

(25-78)4′-{4-bromo-2-ethoxy-5-[((S)-2-mercapto-4-methylpentanoylamino)methyl]-imidazol-1-ylmethyl}biphenyl-2-carboxylicacid.

(25-79) thioacetic acidS—[(S)-1-({2-ethoxy-5-ethyl-3-[2′-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-3H-imidazol-4-ylmethyl}carbamoyl)-3-methylbutyl]ester.

(25-80) (3)-2-mercapto-4-methylpentanoic acid{5-chloro-2-ethoxy-3-[3-fluoro-2′-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-3H-imidazol-4-ylmethyl}amide.

(25-81) (S)-2-mercapto-4-methylpentanoic acid{5-cyclopropyl-2-ethoxy-3-[3-fluoro-2′-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-3H-imidazol-4-ylmethyl}amide.

(25-82)4′-{4-chloro-5-[((S)-2-mercapto-4-methylpentanoylamino)methyl]-2-methoxy-imidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicacid.

(25-83)4′-{4-chloro-5-[((S)-2-mercapto-4-methylpentanoylamino)methyl]-2-propoxy-imidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicacid.

(25-84)4′-{4-chloro-5-[((S)-2-mercaptomethyl-4-methylpentanoylamino)methyl]-2-methoxyimidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicacid.

(25-85)4′-{4-chloro-5-[((S)-2-mercaptomethyl-4-methylpentanoylamino)methyl]-2-propoxyimidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicacid.

(25-86)4′-{5-[((S)-2-acetylsulfanyl-4-methylpentanoylamino)methyl]-2-ethoxy-4-ethyl-imidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicacid methyl ester.

(25-87)4′-{2-ethoxy-4-ethyl-5-[((S)-2-mercapto-4-methylpentanoylamino)methyl]-imidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicacid methyl ester.

(25-88) (S)-2-mercapto-4-methyl-pentanoic acid[2-ethoxy-5-ethyl-3-(3-fluoro-2′-trifluoromethanesulfonylaminocarbonylbiphenyl-4-ylmethyl)-3H-imidazol-4-ylmethyl]-amide.

(25-89)4′-{2-ethoxy-4-ethyl-5-[((R)-2-mercapto-3-phenylpropionylamino)methyl]-imidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicacid.

(25-90)4′-{2-ethoxy-4-ethyl-5-[(4,4,4-trifluoro-2-mercaptobutyrylamino)methyl]-imidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicacid.

(25-91)4′-{2-ethoxy-4-ethyl-5-[(5,5,5-trifluoro-2-mercaptopentanoylamino)methyl]-imidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicacid.

(25-92)4′-(2-ethoxy-4-ethyl-5-{[2-(2-fluorophenyl)-2-mercaptoacetylamino]methyl}-imidazol-1-ylmethyl)-3′-fluorobiphenyl-2-carboxylicacid.

(25-93)4′-(5-{[3-(4-chlorophenyl)-2-mercaptopropionylamino]methyl}-2-ethoxy-4-ethylimidazol-1-ylmethyl)-3′-fluorobiphenyl-2-carboxylicacid.

(25-94)4′-(2-ethoxy-4-ethyl-5-{[3-(2-fluorophenyl)-2-mercaptopropionylamino]-methyl}-imidazol-1-ylmethyl)-3′-fluorobiphenyl-2-carboxylicacid.

(25-95)4′-(2-ethoxy-4-ethyl-5-{[3-(3-fluorophenyl)-2-mercaptopropionylamino]-methyl}imidazol-1-ylmethyl)-3′-fluorobiphenyl-2-carboxylicacid.

Following the procedures described in the examples above, andsubstituting the appropriate starting materials and reagents, compound25-96 can also readily be prepared:

(25-96)4′-(2-ethoxy-4-ethyl-5-{[((S)-2-mercapto-4-methylpentanoyl)methylamino]-methyl}-imidazol-1-ylmethyl)biphenyl-2-carboxylicacid.

Example 26

Following the procedures described in the examples above, andsubstituting the appropriate starting materials and reagents, compounds26-1 to 26-10, having the following formula, were also prepared:

Ex. R R¹ R² R³ R⁵ R⁶ 26-1 3-fluoro —SO₂—NHC(O)—CH₃ H —O—CH₂CH₃ —CH₂SHbenzyl 26-2 3′-fluoro —COOH H —O—CH₂CH₃ —CH₂SH 3,5-difluorobenzyl 26-33′-fluoro —COOH H —O—CH₂CH₃ —CH₂SH 2-fluorobenzyl 26-4 3′-fluoro —COOH H—O—CH₂CH₃ —CH₂SH 3-fluorobenzyl 26-5 3′-fluoro —COOH H —O—CH₂CH₃ —CH₂SH2-chlorobenzyl 26-6 3′-fluoro —COOH H —O—CH₂CH₃ —CH₂SH 3-chlorobenzyl26-7 3′-fluoro —COOH H —O—CH₂CH₃ —CH₂SH 4-fluorobenzyl 26-8 3′-fluoro—COOH H —O—CH₂CH₃ —CH₂SH —CH₂—CH(CH₃)₂ 26-9 3′-fluoro —COOH —C(CH₃)₂—OH—(CH₂)₂CH₃ —CH₂SH benzyl 26-10 3′-fluoro —COOH —C(CH₃)₂—OH —(CH₂)₂CH₃—CH₂SH 2-methylbenzyl

(26-1)3-(2′-acetylsulfamoyl-3-fluorobiphenyl-4-ylmethyl)-2-ethoxy-3H-imidazole-4-carboxylicacid ((R)-1-benzyl-2-mercaptoethyl)-amide. MS m/z: [M+H⁺] calcd forC₃₀H₃₁FN₄O₅S₂, 611.17. found 611.4.

(26-2)4′-{5-[(R)-1-(3,5-difluorobenzyl)-2-mercapto-ethylcarbamoyl]-2-ethoxy-imidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₂₉H₂₆F₃N₃O₄S, 570.16. found 570.6.

(26-3)4′-{2-ethoxy-5-[(R)-1-(2-fluorobenzyl)-2-mercapto-ethylcarbamoyl]-imidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₂₉H₂₇F₂N₃O₄S, 552.17. found 552.8.

(26-4)4′-{2-ethoxy-5-[(R)-1-(3-fluorobenzyl)-2-mercapto-ethylcarbamoyl]-imidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₂₉H₂₇F₂N₃O₄S, 552.17. found 552.8.

(26-5)4′-{5-[(R)-1-(2-chlorobenzyl)-2-mercaptoethylcarbamoyl]-2-ethoxy-imidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₂₉H₂₇ClFN₃O₄S, 568.14. found 568.3.

(26-6)4′-{5-[(R)-1-(3-chlorobenzyl)-2-mercaptoethylcarbamoyl]-2-ethoxy-imidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₂₉H₂₇ClFN₃O₄S, 568.14. found 568.2.

(26-7)4′-{2-ethoxy-5-[(R)-2-(4-fluorophenyl)-1-mercaptomethylethylcarbamoyl]-imidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₂₉H₂₇F₂N₃O₄S, 552.17. found 552.8.

(26-8)4′-[2-ethoxy-5-((R)-1-mercaptomethyl-2-o-tolylethylcarbamoyl)-imidazol-1-ylmethyl]-3′-fluorobiphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₀H₃₀FN₃O₄S, 548.19. found 548.6.

(26-9)4′-[5-((R)-1-benzyl-2-mercapto-ethylcarbamoyl)-4-(1-hydroxy-1-methylethyl)-2-propylimidazol-1-ylmethyl]-3′-fluorobiphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₃H₃₆FN₃O₄S, 590.24. found 590.4.

(26-10)3′-fluoro-4′-[4-(1-hydroxy-1-methyl-ethyl)-5-((R)-1-mercaptomethyl-3-methylbutylcarbamoyl)-2-propylimidazol-1-ylmethyl]-biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₀H₃₈FN₃O₄S, 556.26. found 556.4.

Preparation 191-(4-t-Butoxycarbonylbenzyl)-5-propyl-1H-pyrazole-3-carboxylic Acid

4-Bromomethylbenzoic acid t-butyl ester (19a): 4-Bromomethylbenzoylbromide (13.9 g, 50 mmol, 1.0 eq) was added to 50 mL of DCM, followed byt-butanol (9.6 mL, 100 mmol, 2.0 eq) and the mixture was slowly warmedto room temperature. After 20 hours, the reaction was concentrated underreduced pressure, dissolved into 350 mL EtOAc, washed with 400 mL sat.bicarbonate and 200 mL saturated aqueous NaCl. The organic was driedover MgSO₄, filtered, and concentrated under reduced pressure to yieldintermediate (19a) as a semisolid (7.3 g).

1-(4-t-Butoxycarbonyl-benzyl)-5-propyl-1H-pyrazole-3-carboxylic acidethyl ester (19b): To the recovered intermediate (19a) (1.4 g, 5 mmol,1.0 eq) dissolved into 15 mL DMF, was added5-propyl-1H-pyrazole-3-carboxylic acid ethyl ester (910 mg, 5.0 mmol,1.0 eq) and potassium carbonate (0.8 g, 5.5 mmol, 1.1 eq) and themixture was stirred at room temperature for 16 hours. The mixture wasthen added to 50 mL of 10% aq. LiCl solution and extracted with 50 mLEtOAc. The organic was dried over MgSO₄, and concentrated under reducedpressure to yield intermediate (19b) and its regioisomer in a 1:1 ratio.The recovered regioisomers were dissolved into 25 mL MeOH. To this wasadded 10 mL of 1M NaOH and the mixture was stirred at room temperatureover night. The mixture was acidified with acetic acid and concentratedunder reduced pressure. The recovered oil was purified by preparatoryHPLC, producing the desired regioisomer of the title compound as a whitesolid TFA salt after lyophilization (230 mg). ¹H NMR (DMSO) 0.89 (t,3H), 1.52 (s, 9H), 5.71 (s, 2H), 6.71 (s, 1H), 7.15 (d, 2H), 7.83 (d,2H), 13.28 (br s, 1H).

Preparation 20 Thioacetic acid S—((S)-2-amino-3-phenylpropyl) Ester

((S)-1-Benzyl-2-hydroxyethyl)carbamic acid t-butyl ester (20a):(S)-2-Amino-3-phenyl-propan-1-ol (5 g, 33 mmol, 1.0 eq) was dissolvedinto 100 mL MeOH. To this was added di-t-butyldicarbonate (7.6 g, 35mmol, 1.1 eq) and the mixture was stirred at room temperature for 4hours. The mixture was then concentrated under reduced pressure,dissolved into EtOAc, and washed with 1M H₃PO₄ and saturated aqueousNaCl. After drying over MgSO₄, the organic was filtered and concentratedunder reduced pressure to yield crude intermediate (20a) (8.5 g).

Toluene-4-sulfonic acid (S)-2-t-butoxycarbonylamino-3-phenylpropyl ester(20b): The recovered intermediate (20a) (8.5 g, 33 mmol, 1.0 eq) wasdissolved into 70 mL pyridine containing potassium hydroxide (2.1 g, 37mmol, 1.1 eq) and the mixture was chilled in an ice bath. Tosyl chloride(7.1 g, 37 mmol, 1.1 eq) was added and the mixture was stirred at 0° C.for 2 hours then refrigerated overnight. The mixture was filtered andthe filtrate was concentrated under reduced pressure. The recoveredresidue was dissolved into 300 mL EtOAc, washed with 2×200 mL 1M H₃PO₄,saturated bicarbonate, and saturated aqueous NaCl. The organic was driedover MgSO₄ and concentrated under reduced pressure to yield intermediate(20b) (10.3 g) as a pale brown oil.

Intermediate (20b) (10.3 g, 25 mmol, 1.0 eq) was added to a solution ofthioacetic acid (2.2 mL, 30 mmol, 1.2 eq) and KOH (1.7 g, 30 mmol, 1.2eq) in 80 mL DMF cooled to 0° C. The mixture was stirred at 0° C. for 2hours, slowly warmed to room temperature, then stirred for 48 hours. Themixture was diluted with water and extracted with EtOAc. The materialwas washed 2× with sat. bicarbonate and saturated aqueous NaCl, thendried over MgSO₄. The organic was filtered and concentrated underreduced pressure to yield an oil (7.1 g). This oil was then dissolvedinto 30 mL of 1:1 TFA:DCM and stirred at room temperature for 1 hour.The mixture was concentrated to produce the title compound in aquantitative yield.

Example 274-[5-((S)-1-Benzyl-2-mercaptoethylcarbamoyl)-3-propylpyrazol-1-ylmethyl]benzoicacid (compound 27-1; R⁵=—CH₂SH)

1-(4-t-Butoxycarbonylbenzyl)-5-propyl-1H-pyrazole-3-carboxylic acid (460mg, 0.1 mmol, 1.0 eq) was dissolved into 1.0 mL DMF. To this was addedHATU and the mixture was shaken for 10 minutes. Thioacetic acidS—((S)-2-amino-3-phenylpropyl) ester (320 mg, 0.1 mmol, 1.0 eq) wasadded, followed by DIPEA (520 μL, 0.3 mmol, 3.0 eq). The mixture wasshaken over night, concentrated under reduced pressure, and the residueredissolved into 3 mL of 4N HCl in dioxane and shaken for 4 hours. Themixture was again concentrated under reduced pressure, and dissolvedinto 2.0 mL MeOH. The mixture was purged with nitrogen, 1.0 mL of 3MNaOH was added, and the mixture was stirred at room temperature for 2hours. The mixture was acidified with 0.5 mL acetic acid andconcentrated under reduced pressure. The recovered oil was purified byreverse HPLC to yield compound 27-1 as a white solid (1.3 mg). MS m/z:[M+H⁺] calc'd for C₂₄H₂₇N₃O₃S, 438.2. found 438.

Compound (27-2) was prepared in a similar manner:4-[5-((S)-1-hydroxycarbamoyl-2-phenylethylcarbamoyl)-3-propylpyrazol-1-ylmethyl]benzoicacid (R⁵=—C(O)N(OH)H). MS m/z: [M+H⁺] calcd for C₂₄H₂₆N₄O₅, 451.19.found 451.

Preparation 21[1-Ethoxy-but-(E)-ylidene-hydrazinocarbonylmethyl]carbamic acid t-ButylEster

Ethyl butyrimidate.HCl (21a): 1-cyanopropane (20 g, 290 mmol) was mixedwith butylether (250 mL) and cooled to 0° C. Ethanol (18.6 mL, 320 mmol)was added and HCl gas was bubbled through the mixture for 45 minutes.The mixture was then sealed and stored at 5° C. overnight. A 100 mLaliquot of the mixture was withdrawn and concentrated to give an oilwhich was dissolved in MeCN and concentrated until crystallization wasinitiated. EtOAc was added and the mixture was maintained at −20° C.overnight. The resulting solidified mixture was diluted with EtOAc,filtered, and washed with diethyl ether under nitrogen to give 7.8 g ofcompound (21a) as a white solid. ¹H-NMR (DMSO): 11.5 ppm (bs, 2H), 4.45ppm (q, 2H), 2.6 ppm (t, 2H), 1.65 ppm (m, 2H), 1.3 ppm (t, 3H), 0.9 ppm(t, 3H).

Compound (21a) (3.0 g, 19.9 mmol) was dissolved in ethanol (10 mL) andcooled to −78° C. Hydrazinocarbonylmethylcarbamic acid t-butyl ester inethanol (10 mL) was added dropwise over 20 minutes. The mixture was thencapped and stored at 4° C. for 4 days. The precipitant was filtered offand the solvent was concentrated to obtain the title compound (4.0 g).

Preparation 22 4′-Aminomethylbiphenyl-2-carboxylic Acid t-Butyl Ester

4′-(1,3-Dioxo-1,3-dihydroisoindol-2-ylmethyl)biphenyl-2-carboxylic Acidt-Butyl Ester (22a): 4′-Bromomethylbiphenyl-2-carboxylic acid t-butylester (4.0 g, 11.5 mmol) and potassium phthalimide were combined anddissolved in DMF (30 mL), and the mixture was heated at 50° C. for twodays. The mixture was then cooled to room temperature and the reactionquenched with water (30 mL). The mixture was then extracted with EtOAc,and washed with a 10% aqueous lithium chloride solution. The organiclayer was dried over MgSO₄, filtered and concentrated to obtainintermediate (22a) (4.8 g). MS m/z: [M+H⁺] calcd for C₂₆H₂₃NO₄, 414.5.found 414.3.

Intermediate (22a) (4.8 g, 11.5 mmol) and hydrazine (5.0 mL, 100 mmol)were dissolved in ethanol (50 mL) and heated at 80° C. for 5 hours. Themixture was then cooled to room temperature, the precipitant wasfiltered off and the solvent was concentrated to obtain the titlecompound (3.4 g). MS m/z: [M+H⁺] calcd for C₁₈H₂₁NO₂, 284.4. found284.3.

Preparation 234′-(3-Aminomethyl-5-propyl[1,2,4]triazol-4-ylmethyl)biphenyl-2-carboxylicAcid

4′-[3-(t-Butoxycarbonylaminomethyl)-5-propyl-[1,2,4]triazol-4-ylmethyl]biphenyl-2-carboxylicacid t-butyl ester (23a): 4′-Aminomethylbiphenyl-2-carboxylic acidt-butyl ester (1.5 g, 5.2 mmol) and[1-ethoxy-but-(E)-ylidene-hydrazinocarbonylmethyl] carbamic acid t-butylester (1.0 g, 3.5 mmol) were combined and dissolved in ethanol (50 mL).The mixture was heated at 50° C. for 2 hours and then 70° C. overnight.The mixture was then cooled and concentrated. The product was purifiedby silica gel chromatography (0-20% MeOH:DCM) to obtain intermediate(23a) (400 g). MS m/z: [M+H⁺] calcd for C₂₉H₃₈N₄O₄, 507.6. found 507.3.

Intermediate (23a) (400 mg, 790 μmol) was dissolved in a mixture of TFA(1 mL) and DCM (2 mL). The mixture was stirred at room temperature for 4hours and was then concentrated. The product was purified by preparativeHPLC (10-50% MeCN in water w/0.05% TFA) to obtain the title compound(120 mg). MS m/z: [M+H⁺] calcd for C₂₀H₂₂N₄O₂, 351.4. found 351.2.

Example 284′-{3-[(2-Acetylsulfanylmethyl-4-methylpentanoylamino)methyl]-5-propyl[1,2,4]triazol-4-ylmethyl}biphenyl-2-carboxylicAcid (28a; R^(5a)=—C(O)CH₃) and4′-{3-[(2-Mercaptomethyl-4-methylpentanoylamino)methyl]-5-propyl[1,2,4]triazol-4-ylmethyl}biphenyl-2-carboxylic Acid (28b; R^(5a)═H)

2-Acetylsulfanylmethyl-4-methylpentanoic acid (66.0 mg, 0.314 mmol) andHATU (119 mg, 314 μmol) were combined and dissolved in DMF (2 mL) andstirred for 15 minutes. DIPEA (50 μL, 290 μmol) was then added and themixture stirred at room temperature for 30 minutes.4′-(3-Aminomethyl-5-propyl-1,2,4-triazol-4-ylmethyl)biphenyl-2-carboxylicacid (100 mg, 290 μmol) in DMF (1 mL) was added to the mixture, followedby the addition of a second equivalent of DIPEA (50 μL, 290 μmol). Themixture was stirred at room temperature overnight. Water (5 mL) wasadded to quench the reaction, and the mixture was then extracted withEtOAc and washed with a 10% aqueous lithium chloride solution. Theorganic layer was dried over MgSO₄, filtered and concentrated to obtainintermediate (28a) (50 mg) which was carried directly on to the nextreaction. MS m/z: [M+H⁺] calcd for C₂₉H₃₆N₄O₄S, 537.7. found 537.3.

Intermediate (28a) (50 mg, 930 μmol) was dissolved in MeOH (2 mL) and 1N sodium bicarbonate (2 mL), and stirred at room temperature undernitrogen for 30 minutes. The reaction was quenched with acetic acid andthe resulting mixture concentrated. The product was purified bypreparative HPLC (30-70% MeCN in water w/0.05% TFA) to obtain the titlecompound (9 mg). MS m/z: [M+H⁺] calcd for C₂₇H₃₄N₄O₃S, 494.7. found494.4.

Example 29

Following the procedures described in the examples above, andsubstituting the appropriate starting materials and reagents, compounds29-1 to 29-4, having the following formula, were also prepared:

(29-1)4′-{3-[(2-hydroxycarbamoyl-4-methylpentanoylamino)methyl]-5-propyl[1,2,4]triazol-4-ylmethyl}biphenyl-2-carboxylic acid (R⁵=—C(O)N(OH)H;R⁶=—CH₂CH(CH₃)₂). MS m/z: [M+H⁺] calcd for C₂₇H₃₃N₅O₅, 508.25. found508.4.

(29-2)4′-{3-[(2-hydroxycarbamoyl-3-phenylpropionylamino)methyl]-5-propyl[1,2,4]triazol-4-ylmethyl}biphenyl-2-carboxylic acid (R⁵=—C(O)N(OH)H;R⁶=benzyl). MS m/z: [M+H⁺] calcd for C₃₀H₃₁N₅O₅, 542.23. found 542.2.

(29-3) 4′-{3-[(2-mercaptomethyl-3-phenylpropionylamino)methyl]-5-propyl[1,2,4]triazol-4-ylmethyl}biphenyl-2-carboxylic acid (R⁵=—CH₂SH; R⁶=benzyl). MSm/z: [M+H⁺] calcd for C₃₀H₃₂N₄O₃S, 529.22. found 529.

(29-4)4′-{3-[((R)-2-mercaptomethyl-4-methylpentanoylamino)methyl]-5-propyl[1,2,4]triazol-4-ylmethyl}biphenyl-2-carboxylic acid (R⁵=—CH₂SH;R⁶=—CH₂CH(CH₃)₂). MS m/z: [M+H⁺] calcd for C₂₇H₃₄N₄O₃S, 495.24. found495.2.

Example 30

Following the procedures described in the examples above, andsubstituting the appropriate starting materials and reagents, compounds30-1 to 30-4, having the following formula, were also prepared:

(30-1)4-{3-[(2-mercaptomethyl-4-methylpentanoylamino)methyl]-5-propyl[1,2,4]triazol-4-ylmethyl}benzoic acid (R⁵=—CH₂SH; R⁶=—CH₂CH(CH₃)₂). MS m/z:[M+H⁺] calcd for C₂₁H₃₀N₄O₃S, 419.20. found 419.2.

(30-2)4-{3-[(2-mercaptomethyl-3-phenylpropionylamino)methyl]-5-propyl[1,2,4]triazol-4-ylmethyl}benzoic acid (R⁵=—CH₂SH; R⁶=benzyl). MS m/z: [M+H⁴]calcd for C₂₄H₂₈N₄O₃S, 453.19. found 453.2.

(30-3)4-{3-[(2-hydroxycarbamoyl-4-methylpentanoylamino)methyl]-5-propyl[1,2,4]triazol-4-ylmethyl}benzoic acid (R⁵=—C(O)N(OH)H; R⁶=—CH₂CH(CH₃)₂). MSm/z: [M+H⁺] calcd for C₂₁H₂₉N₅O₅, 432.22. found 432.2.

(30-4)4-{3-[(2-hydroxycarbamoyl-3-phenylpropionylamino)methyl]-5-propyl[1,2,4]triazol-4-ylmethyl}benzoic acid (R⁵=—C(O)N(OH)H; R⁶=benzyl). MS m/z:[M+H⁺] calcd for C₂₄H₂₇N₅O₅, 466.20. found 466.2.

Preparation 24 (6-Butyl-2-oxo-1,2-dihydropyridin-3-ylmethyl)carbamicAcid t-Butyl Ester

6-Butyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (24a): A solution ofdiisopropylamine (20.5 mL, 2 eq) in THF (200 mL) was cooled to −5° C.n-Butyllithium (53.5 mL, 2.9 M in hexanes, 2 eq) was added over 10minutes. The solution was allowed to rise to 0° C., stirred for 0.5hours, then cooled again to −30° C. 3-Cyano-6-methyl-2(1H)pyridinone (10g, 75 mmol) was added portionwise, and the mixture was allowed to warmto room temperature and stirred for 2 hours. The solution was thencooled to −50° C., and 1-bromopropane (6.8 mL, 1 eq) was added. Thesolution was allowed to warm to room temperature, stirred for 1 hour,and then quenched with a saturated ammonium chloride solution. The THFwas evaporated and the aqueous phase extracted with DCM (2×100 mL). Theorganics were washed with saturated aqueous NaCl, dried over Na₂SO₄, andevaporated to yield intermediate (24a) as an orange solid (10.8 g, 61mmol), which was used without further purification. MS m/z: [M+H⁺] calcdfor C₁₀H₁₂N₂O, 177.2. found 177.0. ¹H-NMR (DMSO) 7.87 (1H, d), 6.05 (1H,d), 2.38 (2H, t), 1.41 (2H, m), 1.15 (2H, m), 0.93 (1H, d), 0.73 (3H,t).

3-Aminomethyl-6-butyl-1H-pyridin-2-one (24b): intermediate (24a) (180mg, 1 mmol) was dissolved in MeOH (10 mL). Aqueous ammonia (1 mL) wasadded, followed by wet Raney Nickel (100 mg). The mixture was stirred atroom temperature under hydrogen for 3 hours. The mixture was thenfiltered and the filtrate evaporated to yield intermediate (24b) (157mg, 870 which was used without further purification. MS m/z: [M+H⁺]calcd for C₁₀H₁₇N₂O, 181.3. found 181.3.

Intermediate (24b) (157 mg, 0.87 mmol) was dissolved in DCM (10 mL).Triethylamine (121 μL, 1 eq) was added, followed by di-tert-butyldicarbonate (189 mg, 1 eq). The mixture was stirred at room temperaturefor 16 hours. The solvent was then evaporated and the residue purifiedby silica gel chromatography (1:1 EtOAc:hexane) to afford the titlecompound (200 mg, 710 μmol). MS m/z: [M+H⁺] calcd for C₁₅H₂₅N₂O₃, 281.4.found 281.3.

Preparation 254′-(3-Aminomethyl-6-butyl-2-oxo-2H-pyridin-1-ylmethyl)biphenyl-2-carboxylicAcid.HCl

4′-[3-(t-Butoxycarbonylaminomethyl)-6-butyl-2-oxo-2H-pyridin-1-ylmethyl]biphenyl-2-carboxylicAcid t-Butyl Ester (25a):(6-Butyl-2-oxo-1,2-dihydropyridin-3-ylmethyl)carbamic acid t-butyl ester(200 mg, 0.71 mmol) was dissolved in THF (5 mL) and cooled to −5° C.n-Butyllithium (285 μL, 2.5M solution in hexanes, 1 eq) was added, andthe mixture was stirred at −5° C. for 5 minutes.4′-Bromomethylbiphenyl-2-carboxylic acid t-butyl ester (247 mg, 1 eq)was added, and solution was warmed to reflux and stirred for 72 hours.The solution was allowed to cool, the solvent evaporated and the residuepurified by silica gel chromatography (3:1 hexanes:EtOAc) to yieldintermediate (25a) as a white solid (180 mg, 330 μmol). MS m/z: [M+H⁺]calcd for C₃₃H₄₃N₂O₅, 547.7. found 547.3.

Intermediate (25a) (180 mg, 0.33 mmol) was dissolved in DCM (3 mL) andTFA (3 mL). The mixture was stirred at room temperature for 16 hours,and then evaporated to dryness. The residue was dissolved in MeCN andwater, and HCl (1M, 0.5 mL) was added. The solution was lyophilized toyield the title compound (133 mg, 310 μmol) as a white solid, which wasused without further purification. MS m/z: [M+H⁺] calcd for C₂₄H₂₇N₂O₃,391.5. found 391.3.

Example 314′-{6-Butyl-3-[(2-mercaptomethyl-4-methylpentanoylamino)methyl]-2-oxo-2H-pyridin-1-ylmethyl}biphenyl-2-carboxylic(compound 31-1. R⁶=—CH₂CH(CH₃)₂)

2-Acetylsulfanylmethyl-4-methyl-pentanoic acid (24 mg, 1.1 eq) and HATU(44 mg, 1.1 eq) were dissolved in DMF (2 mL). DIPEA (740 μL, 4 eq) wasadded, and the mixture was stirred at room temperature for 15 minutes.4′-(3-Aminomethyl-6-butyl-2-oxo-2H-pyridin-1-ylmethyl)biphenyl-2-carboxylicacid HCl (45 mg, 0.1 mmol) was added, and the solution was stirred atroom temperature for 4 hours. The reaction was quenched with water (8mL) and concentrated HCl (3 drops), and the mixture extracted with EtOAc(10 mL). The organic layer was dried over Na₂SO₄, and evaporated. Theresidue was dissolved in MeOH (1 mL) and 1M NaOH (3 mL). The solutionwas stirred under nitrogen for 20 minutes, and the reaction was thenquenched with acetic acid (2 mL). The MeOH was evaporated, and theaqueous component extracted with EtOAc (10 mL). The solvent wasevaporated and the residue purified by reverse phase chromatography toafford the title compound (7.5 mg, 140 μmol). MS m/z: [M+H⁺] calcd forC₃₁H₃₉N₂O₄S, 535.7. found 535.2.

Compound (31-2) was prepared in a similar manner:4′-{3-[(2-benzyl-3-mercaptopropionylamino)methyl]-6-butyl-2-oxo-2H-pyridin-1-ylmethyl}biphenyl-2-carboxylicacid (R⁶=benzyl). MS m/z: [M+H⁺] calcd for C₃₄H₃₆N₂O₄S, 569.24. found570.2.

Preparation 26 4-chloro-2-ethoxyimidazole-5-carboxaldehyde

4-Bromo-5-chloro-2-ethoxy-1-(2-trimethylsilanylethoxymethyl)-1H-imidazole(26a): n-Butyllithium (2.5M in hexanes, 3.3 mL) was added to a solutionof 4,5-dibromo-2-ethoxy-1-(2-trimethylsilanylethoxymethyl)-1H-imidazole(3.0 g, 7.5 mmol) and N,N,N′,N′-tetramethylethylenediamine (1.2 mL, 8.3mmol) in THF (20 mL) at −78° C. After 3 minutes, a solution ofhexachloroethane (2.3 g, 9.7 mmol) in THF (8 mL) was added at −78° C.The mixture was stirred at −78° C. for 1 hour and was then allowed towarm to room temperature. Saturated aq. NH₄C1 (3 mL) was added and themixture was concentrated in vacuo. The mixture was extracted with EtOAc(2×100 mL) and sat. aq. NaHCO₃ (30 mL). The combined organic fractionswere dried over Na₂SO₄, filtered, and concentrated in vacuo. Silica gelchromatography (EtOAc:hexane) afforded intermediate (26a) (2.3 g).

5-Chloro-2-ethoxy-1-(2-trimethylsilanylethoxymethyl)-1H-imidazole-4-carbaldehyde(26b): n-Butyllithium (2.5M in hexanes, 1.2 mL) was added to a solutionof intermediate (26a) (1.0 g, 2.8 mmol) andN,N,N′,N′-tetramethylethylenediamine (0.5 mL, 3.1 mmol) in THF (8 mL) at−78° C. DMF (0.3 mL, 3.4 mmol) was added after 3 minutes. The mixturewas stirred at −78° C. for 1 hour. The mixture was allowed to warm toroom temperature over 30 minutes. Saturated aq. NH₄OH (1 mL) was addedand the mixture was concentrated in vacuo. The mixture was extractedwith DCM (2×30 mL) and 0.5M PO₃H₄ (10 mL). The combined organicfractions were washed with sat. aq. NaHCO₃ (20 mL), dried over Na₂SO₄,filtered, and concentrated in vacuo. Silica gel chromatography(EtOAc:hexane) afforded intermediate (26b) (600 mg).

A solution of intermediate (26b) (500 mg, 2.0 mmol) in DCM (2 mL) andTFA (4 mL) was stirred at room temperature for 3 hours. The mixture wasconcentrated in vacuo. The concentrate was extracted with DCM (2×8 mL)and sat. aq. NaHCO₃ (5 mL). The combined organic fractions were driedover Na₂SO₄, filtered, and concentrated in vacuo to afford the crudetitle compound (298 mg).

Preparation 274′-(5-Aminomethyl-4-chloro-2-ethoxyimidazol-1-ylmethyl)-3′-fluorobiphenyl-2-carboxylicacid t-Butyl Ester

4′-(4-Chloro-2-ethoxy-5-formyl-imidazol-1-ylmethyl)-3′-fluoro-biphenyl-2-carboxylicacid tert-butyl ester (27a): A solution of4-chloro-2-ethoxyimidazole-5-carboxaldehyde (295.0 mg, 1.7 mmol),4′-bromomethyl-3′-fluorobiphenyl-2-carboxylic acid t-butyl ester (617mg, 1.7 mmol) and potassium carbonate (467 mg, 3.4 mmol) in DMF (6 mL)was stirred overnight. The mixture was filtered and concentrated invacuo. Silica gel chromatography (hexane:EtOAc) afforded intermediate(27a) (598 mg).

4′-[4-Chloro-2-ethoxy-5-(hydroxyiminomethyl)imidazol-1-ylmethyl]-3′-fluorobiphenyl-2-carboxylicacid t-butyl ester (27b): Hydroxylamine hydrochloride (185 mg) was addedto a solution of intermediate (27) (610.0 mg, 1.3 mmol) in pyridine (8mL) and water (3 mL). After 1 hour, water (20 mL) was added and theresulting precipitate was filtered. The solid was dried in vacuo toafford crude intermediate (27b) (468 mg).

Titanium(III) chloride (448 mg, 2.90 mmol) was added to a solution ofintermediate (27b) (459.0 mg, 1.0 mmol), NaBH₃CN (274 mg, 4.4 mmol) andammonium acetate (164 mg, 2.1 mmol) in MeOH (8 mL) at 0° C. The mixturewas stirred at room temperature for 3 hours. The mixture was added to asolution of sat. aq. ammonia (15 mL) and MeOH (15 mL). The solution wasfiltered, and concentrated in vacuo. The concentrate was extracted withDCM (2×80 mL) and sat. aq. NaHCO₃ (50 mL). The combined organic layerswere dried over Na₂SO₄, filtered and concentrated in vacuo. Silica gelchromatography [DCM:MeOH (5% triethylamine)] afforded the title compound(85 mg).

Example 324′-{4-Chloro-2-ethoxy-5-[((S)-2-mercapto-4-methylpentanoylamino)methyl]imidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicAcid.C₂HF₃O₂

EDC (30 μL, 0.2 mmol) was added to a solution of4′-(5-aminomethyl-4-chloro-2-ethoxyimidazol-1-ylmethyl)-3′-fluorobiphenyl-2-carboxylicacid t-butyl ester (80.0 mg, 0.2 mmol),(S)-2-acetylsulfanyl-4-methylpentanoic acid (33.1 mg, 0.2 mmol),1-Hydroxy-7-azabenzotriazole (23.7 mg, 0.2 mmol), and 4-methylmorpholine(19.1 μL, 0.2 mmol) in DMF (1 mL) at 0° C. The mixture was stirredovernight at room temperature. The mixture was extracted with EtOAc(2×10 mL) and 0.5M aq. HCl (10 mL). The combined organic fractions weredried over sodium sulfate and concentrated in vacuo to afford an oil. Asolution of the oil in DCM (2 mL) and TFA (4 mL) was stirred at roomtemperature. After 2 hours, the mixture was concentrated in vacuo toafford an oil. A solution of the oil in MeOH (2 mL) and 1M aq. NaOH (3mL) was stirred under nitrogen for 1.5 hours. The mixture wasneutralized with 6M aq. HCl and was concentrated in vacuo. Reverse phaseHPLC afforded the title compound (9.7 mg). MS m/z: [M+H⁺] calcd forC₂₆H₂₉ClFN₃O₄S, 534.16. found: 534.0.

Example 33 Cyclization of4′-{2-ethoxy-4-ethyl-5-[((S)-2-mercapto-4-methylpentanoylamino)methyl]-imidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicacid to form cyclic prodrugs (33-1) and (33-2)

To a solution of4′-{2-ethoxy-4-ethyl-5-[((S)-2-mercapto-4-methylpentanoyl-amino)methyl]imidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylicacid.C₂HF₃O₂ (138 mg, 215 μmol) in methylene chloride (20 mL, 0.3 mol)was added DMAP (27.6 mg, 0.226 mmol) and EDC (43.3 mg, 0.226 mmol). Themixture was stirred at room temperature overnight. After evaporation ofvolatile solvents, the residue was purified by preparative HPLC, toyield the cyclic thioesters as monomer (33-1) and dimer (33-2) in a pureform (>95%).

(33-1) ESMS [M+H⁺] calcd for C₂₈H₃₂FN₃O₃S, 510.22. found 510.6. Anal.HPLC retention time=3.86 min; gradient conditions=25-95% MeCN/H₂O over 5min. ¹H-NMR (CD₃OD, 300 MHz) δ (ppm) 7.60 (m, 1H), 7.54 (m, 1H),7.52-7.48 (m, 2H), 7.40 (m, 1H), 7.36-7.38 (m, 1H), 6.89-6.92 (d, 1H),4.71 (m, 2H), 4.30-4.35 (br d, 1H), 4.20 (br d, 1H), 4.05 (t, 1H),2.60-2.68 (m, 2H), 1.60-1.75 (m, 1H), 1.55-1.60 (m, 4H), 1.43 (m, 1H),1.23 (t, 3H), 0.90 (d, 6H).

(33-2) ESMS [M+H⁴] calcd for C₅₆H₆₄F₂N₆O₆S₂, 1019.44. found 1019.8.Anal. HPLC retention time=4.19 min; gradient conditions 25-95% MeCN/H₂Oover 5 min.

Assay 1 AT₁ and AT₂ Radioligand Binding Assays

These in vitro assays were used to assess the ability of test compoundsto bind to the AT₁ and the AT₂ receptors.

Membrane Preparation from Cells Expressing Human AT₁ or AT₂ Receptors

Chinese hamster ovary (CHO—K1) derived cell lines stably expressing thecloned human AT₁ or AT₂ receptors, respectively, were grown in HAM's-F12medium supplemented with 10% fetal bovine serum, 10 μg/mlpenicillin/streptomycin, and 500 μg/ml geneticin in a 5% CO₂ humidifiedincubator at 37° C. AT₂ receptor expressing cells were grown in theadditional presence of 100 nM PD123,319 (AT₂ antagonist). When culturesreached 80-95% confluence, the cells were washed thoroughly in PBS andlifted with 5 mM EDTA. Cells were pelleted by centrifugation and snapfrozen in MeOH-dry ice and stored at −80° C. until further use.

For membrane preparation, cell pellets were resuspended in lysis buffer(25 mM Tris/HCl pH 7.5 at 4° C., 1 mM EDTA, and one tablet of CompleteProtease Inhibitor Cocktail Tablets with 2 mM EDTA per 50 mL buffer(Roche cat.#1697498, Roche Molecular Biochemicals, Indianapolis, Ind.))and homogenized using a tight-fitting Dounce glass homogenizer (10strokes) on ice. The homogenate was centrifuged at 1000×g, thesupernatant was collected and centrifuged at 20,000×g. The final pelletwas resuspended in membrane buffer (75 mM Tris/HCl pH 7.5, 12.5 mMMgCl₂, 0.3 mM EDTA, 1 mM EGTA, 250 mM sucrose at 4° C.) and homogenizedby extrusion through a 20G gauge needle. Protein concentration of themembrane suspension was determined by the method described in Bradford(1976) Anal Biochem. 72:248-54. Membranes were snap frozen in MeOH-dryice and stored at −80° C. until further use.

Ligand Binding Assay to Determine Compound Affinities for the Human AT₁and AT₂ Angiotensin Receptors

Binding assays were performed in 96-well Acrowell filter plates (PallInc., cat.#5020) in a total assay volume of 100 μL, with 0.2 μg membraneprotein for membranes containing the human AT₁ receptor, or 2 μgmembrane protein for membranes containing the human AT₂ receptor inassay buffer (50 mM Tris/HCl pH 7.5 at 20° C., 5 mM MgCl₂, 25 μM EDTA,0.025% BSA). Saturation binding studies for determination of K_(d)values of the ligand were done using N-terminally Europium-labeledangiotensin-II ([Eu]AngII,H-(Eu-N¹)-Ahx-Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-OH; PerkinElmer, Boston,Mass.) at 8 different concentrations ranging from 0.1 nM to 30 nM.Displacement assays for determination of pK, values of test compoundswere done with [Eu]AngII at 2 nM and 11 different concentrations of drugranging from 1 μM to 10 Drugs were dissolved to a concentration of 1 mMin DMSO and from there serially diluted into assay buffer. Non-specificbinding was determined in the presence of 10 μM unlabeledangiotensin-II. Assays were incubated for 120 minutes in the dark, atroom temperature or 37° C., and binding reactions were terminated byrapid filtration through the Acrowell filter plates followed by threewashes with 200 μL ice cold wash buffer (50 mM Tris/HCl pH 7.5 at 4° C.,5 mM MgCl₂) using a Waters filtration manifold. Plates were tapped dryand incubated with 50 μl DELFIA Enhancement Solution (PerkinElmercat.#4001-0010) at room temperature for 5 minutes on a shaker.Filter-bound [Eu]AngII was quantitated immediately on a Fusion platereader (PerkinElmer) using Time Resolved Fluorescence (TRF). Bindingdata were analyzed by nonlinear regression analysis with the GraphPadPrism Software package (GraphPad Software, Inc., San Diego, Calif.)using the 3-parameter model for one-site competition. The BOTTOM (curveminimum) was fixed to the value for nonspecific binding, as determinedin the presence of 10 μM angiotensin II. K_(i) values for drugs werecalculated from observed IC₅₀ values and the K_(d) value of [Eu]AngIIaccording to the Cheng-Prusoff equation described in Cheng et al. (1973)Biochem Pharmacol. 22(23):3099-108. Selectivities of test compounds forthe AT₁ receptor over the AT₂ receptor were calculated as the ratio ofAT₂K_(i)/AT₁K_(i). Binding affinities of test compounds were expressedas negative decadic logarithms of the K_(i) values (pK₁).

In this assay, a higher pK_(i) value indicates that the test compoundhas a higher binding affinity for the receptor tested. Exemplarycompounds of the invention that were tested in this assay, typicallywere found to have a pK_(i) at the AT₁ receptor greater than or equal toabout 5.0. For example, the compound of Example 1 was found to have apK_(i) value greater than about 7.0.

Assay 2 In Vitro Assays for the Quantitation of Inhibitor Potencies(IC₅₀) at Human and Rat NEP, and Human ACE

The inhibitory activities of compounds at human and rat NEP and humanACE were determined using in vitro assays as described below.

Extraction of NEP Activity from Rat Kidneys

Rat NEP was prepared from the kidneys of adult Sprague Dawley rats.Whole kidneys were washed in cold PBS and brought up in ice-cold lysisbuffer (1% Triton X-114, 150 mM NaCl, 50 mM Tris pH 7.5; Bordier (1981)J. Biol. Chem. 256:1604-1607) in a ratio of 5 mL of buffer for everygram of kidney. Samples were homogenized using a polytron hand heldtissue grinder on ice. Homogenates were centrifuged at 1000×g in aswinging bucket rotor for 5 minutes at 3° C. The pellet was resuspendedin 20 mL of ice cold lysis buffer and incubated on ice for 30 minutes.Samples (15-20 mL) were then layered onto 25 mL of ice-cold cushionbuffer (6% w/v sucrose, 50 mM pH 7.5 Tris, 150 mM NaCl, 0.06%, TritonX-114), heated to 37° C. for 3-5 minutes and centrifuged at 1000×g in aswinging bucket rotor at room temperature for 3 minutes. The two upperlayers were aspirated off, leaving a viscous oily precipitate containingthe enriched membrane fraction. Glycerol was added to a concentration of50% and samples were stored at −20° C. Protein concentrations werequantitated using a BCA detection system with BSA as a standard.

Enzyme Inhibition Assays

Recombinant human NEP and recombinant human ACE were obtainedcommercially (R&D Systems, Minneapolis, Minn., catalog numbers 1182-ZNand 929-ZN, respectively). The fluorogenic peptide substrate Mca-BK2(Mca-Arg-Pro-Pro-Gly-Phe-Ser-Ala-Phe-Lys(Dnp)-OH; Johnson et al. (2000)Anal. Biochem. 286: 112-118) was used for the human NEP and ACE assays,and Mca-RRL (Mca-DArg-Arg-Leu-(Dnp)-OH; Medeiros et al. (1997) Braz. J.Med. Biol. Res. 30:1157-1162) was used for the rat NEP assay (both fromAnaspec, San Jose, Calif.).

The assays were performed in 384-well white opaque plates at roomtemperature using the respective fluorogenic peptides at a concentrationof 10 μM in assay buffer (50 mM Tris/HCL at 25° C., 100 mM NaCl, 0.01%Tween-20, 1 μM Zn, 0.025% BSA). Human NEP and human ACE were used atconcentrations that resulted in quantitative proteolysis of 5 μM ofMca-BK2 within 20 minutes at room temperature. The rat NEP enzymepreparation was used at a concentration that yielded quantitativeproteolysis of 3 μM of Mca-RRL within 20 minutes at room temperature.

Assays were started by adding 25 μL of enzyme to 12.5 μL of testcompound at 12 concentrations (10 μM to 20 μM). Inhibitors were allowedto equilibrate with the enzyme for 10 minutes before 12.5 μL of thefluorogenic substrates were added to initiate the reaction. Reactionswere terminated by the addition of 10 μL of 3.6% glacial acetic acidafter 20 minutes of incubation. Plates were read on a fluorometer withexcitation and emission wavelengths set to 320 nm and 405 nm,respectively.

Raw data (relative fluorescence units) were normalized to % activityfrom the average high readings (no inhibition, 100% enzyme activity) andaverage low readings (full inhibition, highest inhibitor concentration,0% enzyme activity) using three standard NEP and ACE inhibitors,respectively. Nonlinear regression of the normalized data was performedusing a one site competition model (GraphPad Software, Inc., San Diego,Calif.). Data were reported as pIC₅₀ values.

Exemplary compounds of the invention that were tested in this assay,typically were found to have a pIC₅₀ for the NEP enzyme greater than orequal to about 5.0. For example, the compound of Example 1 has a pIC₅₀value greater than or equal to about 7.0.

Assay 3 Pharmacodynamic (PD) Assay for ACE, AT₁, and NEP Activity inAnesthetized Rats

Male, Sprague Dawley, normotensive rats are anesthetized with 120 mg/kg(i.p.) of inactin. Once anesthetized, the jugular vein, carotid artery(PE 50 tubing) and bladder (URI-1 urinary silicone catheter) arecannulated and a tracheotomy is performed (Teflon Needle, size 14 gauge)to faciliate spontaneous respiration. The animals are then allowed a 60minute stablization period and kept continuously infused with 5 mL/kg/hof saline (0.9%) throughout, to keep them hydrated and ensure urineproduction. Body temperature is maintained throughout the experiment byuse of a heating pad. At the end of the 60 minute stabilization period,the animals are dosed intravenously (i.v.) with two doses of angiotensin(AngI, 1.0 μg/kg, for ACE inhibitor activity; AngII, 0.1 μg/kg, for AT₁receptor antagonist activity) at 15 minutes apart. At 15 minutespost-second dose of angiotensin (AngI or AngII), the animals are treatedwith vehicle or test compound. Five minutes later, the animals areadditionally treated with a bolus i.v. injection of atrial natriureticpeptide (ANP; 30 μg/kg). Urine collection (into pre-weighted eppendorftubes) is started immediately after the ANP treatment and continued for60 minutes. At 30 and 60 minutes into urine collection, the animals arere-challenged with angiotensin (AngI or AngII). Blood pressuremeasurements are done using the Notocord system (Kalamazoo, Mich.).Urine samples are frozen at −20° C. until used for the cGMP assay. UrinecGMP concentrations are determined by Enzyme Immuno Assay using acommercial kit (Assay Designs, Ann Arbor, Mich., Cat. No. 901-013).Urine volume is determined gravimetrically. Urinary cGMP output iscalculated as the product of urine output and urine cGMP concentration.ACE inhibition or AT₁ antagonism is assessed by quantifying the %inhibition of pressor response to AngI or AngII, respectively. NEPinhibition is assessed by quantifying the potentiation of ANP-inducedelevation in urinary cGMP output.

Assay 4 In Vivo Evaluation of Antihypertensive Effects in the ConsciousSHR Model of Hypertension

Spontaneously hypertensive rats (SHR, 14-20 weeks of age) are allowed aminimum of 48 hours acclimation upon arrival at the testing site. Sevendays prior to testing, the animals are either placed on a restrictedlow-salt diet with food containing 0.1% of sodium for sodium depletedSHRs (SD-SHR) or are placed on a normal diet for sodium repleted SHRs(SR—SHR). Two days prior to testing, the animals are surgicallyimplemented with catheters into a carotid artery and the jugular vein(PESO polyethylene tubing) connected via a PE10 polyethylene tubing to aselected silicone tubing (size 0.020 ID×0.037 OD×0.008 wall) for bloodpressure measurement and test compound delivery, respectively. Theanimals are allowed to recover with appropriate post operative care.

On the day of the experiment, the animals are placed in their cages andthe catheters are connected via a swivel to a calibrated pressuretransducer. After 1 hour of acclimation, a baseline measurement is takenover a period of at least five minutes. The animals are then dosed i.v.with vehicle or test compound in ascending cumulative doses every 60minutes followed by a 0.3 mL saline to clear the catheter after eachdose. Data is recorded continuously for the duration of the study usingNotocord software (Kalamazoo, Mich.) and stored as electronic digitalsignals. In some studies, the effects of a single intravenous or oral(gavage) dose are monitored for at least 6 hours after dosing.Parameters measured are blood pressure (systolic, diastolic and meanarterial pressure) and heart rate.

Assay 5 In Vivo Evaluation of Antihypertensive Effects in the ConsciousDOCA-Salt Rat Model of Hypertension

CD rats (male, adult, 200-300 grams, Charles River Laboratory, USA) areallowed a minimum of 48 hours acclimation upon arrival at the testingsite before they are placed on a high salt diet.

One week after the start of the high salt diet, a DOCA-salt pellet (100mg, 21 days release time, Innovative Research of America, Sarasota,Fla.) is implanted subcutaneously and unilateral nephrectomy isperformed. On 16 or 17 days post DOCA-salt pellet implantation, animalsare implanted surgically with catheters into a carotid artery and thejugular vein with a PESO polyethylene tubing, which in turn wasconnected via a PE10 polyethylene tubing to a selected silicone tubing(size 0.020 ID×0.037 OD×0.008 wall) for blood pressure measurement andtest compound delivery, respectively. The animals are allowed to recoverwith appropriate post operative care.

On the day of the experiment, each animal is kept in its cage andconnected via a swivel to a calibrated pressure transducer. After 1 hourof acclimation, a baseline measurement is taken over a period of atleast five minutes. The animals are then dosed i.v. with a vehicle ortest compound in escalating cumulative doses every 60 minutes followedby 0.3 mL of saline to flush the catheter after each dose. In somestudies, the effects of a single intravenous or oral (gavage) dose istested and monitored for at least 6 hours after dosing. Data is recordedcontinuously for the duration of the study using Notocord software(Kalamazoo, Mich.) and stored as electronic digital signals. Parametersmeasured are blood pressure (systolic, diastolic and mean arterialpressure) and heart rate. For cumulative and single dosing, thepercentage change in mean arterial pressure (MAP, mmHg) or heart rate(HR, bpm) is determined as described for Assay 4.

While the present invention has been described with reference tospecific aspects or embodiments thereof, it will be understood by thoseof ordinary skilled in the art that various changes can be made orequivalents can be substituted without departing from the true spiritand scope of the invention. Additionally, to the extent permitted byapplicable patent statues and regulations, all publications, patents andpatent applications cited herein are hereby incorporated by reference intheir entirety to the same extent as if each document had beenindividually incorporated by reference herein.

1. A compound of formula I:

wherein: r is 0, 1 or 2; Ar is selected from:

R¹ is selected from —COOR^(1a), —NHSO₂R^(1b), —SO₂NHR^(1d), —SO₂OH,—C(O)NH—SO₂R^(1c), —P(O)(OH)₂, —CN, —O—CH(R^(1e))—COOH, tetrazol-5-yl,

R^(1a) is H, —C₁₋₆alkyl, —C₁₋₃alkylenearyl, —C₁₋₃alkyleneheteroaryl,—C₃₋₇cycloalkyl, —CH(C₁₋₄alkyl)OC(O)R^(1aa), —C₀₋₆alkylenemorpholine,

R^(1aa) is —O—C₁₋₆alkyl, —O—C₃₋₇cycloalkyl, —NR^(1ab)R^(1ac), or—CH(NH₂)CH₂COOCH₃; R^(1ab) and R^(1ac) are independently selected fromH, —C₁₋₆alkyl, and benzyl, or are taken together as —(CH₂)₃₋₆—; R^(1b)is R^(1c) or —NHC(O)R^(1c); R^(1c) is —C₁₋₆alkyl,—C₀₋₆alkylene-O—R^(1ca), —C₁₋₅alkylene-NR^(1cb)R^(1cc),—C₀₋₄alkylenearyl or —C₀₋₄alkyleneheteroaryl; R^(1ca) is H, —C₁₋₆alkyl,or —C₁₋₆alkylene-O—C₁₋₆alkyl; R^(1cb) and R^(1cc) are independentlyselected from H and —C₁₋₆alkyl, or are taken together as—(CH₂)₂—O—(CH₂)₂— or —(CH₂)₂—N[C(O)CH₃]—(CH₂)₂—; R^(1d) is H, R^(1c),—C(O)R^(1c), or —C(O)NHR^(1c); R^(1e) is —C₁₋₄alkyl or aryl; R² isselected from H, halo, —NO₂, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₃₋₆cycloalkyl,—CN, —C(O)R^(2a), —C₀₋₅alkylene-OR^(2b), —C₀₋₅alkylene-NR^(2c)R^(2d),—C₀₋₃alkylenearyl, and —C₀₋₃alkylene-heteroaryl; where R^(2a) isselected from H, —C₁₋₆alkyl, —C₃₋₆cycloalkyl, —OR^(2b) and—NR^(2c)R^(2d); R^(2b) is selected from H, —C₁₋₆alkyl, —C₃₋₆cycloalkyl,and —C₀₋₁alkylenearyl; and R^(2c) and R^(2d) are independently selectedfrom H, —C₁₋₄alkyl, and —C₀₋₁alkylenearyl; R³ is selected from—C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₃₋₁₀alkynyl, —C₀₋₃alkylene-C₃₋₇cycloalkyl,—C₂₋₃alkenylene-C₃₋₇cycloalkyl, —C₂₋₃alkynylene-C₃₋₇cycloalkyl,—C₀₋₅alkylene-NR^(3a)—C₀₋₅alkylene-R^(3b),—C₀₋₅alkylene-O—C₀₋₅alkylene-R^(3b),—C₀₋₅alkylene-S—C₁₋₅alkylene-R^(3b), and —C₀₋₃alkylenearyl; where R^(3a)is selected from H, —C₁₋₆alkyl, —C₃₋₇cycloalkyl, and —C₀₋₃alkylenearyl;and R^(3b) is selected from H, —C₁₋₆alkyl, —C₃₋₇cycloalkyl,—C₂₋₄alkenyl, —C₂₋₄alkynyl, and aryl; X is —C₁₋₁₂alkylene-, where atleast one —CH₂— moiety in the alkylene is replaced with a —NR^(4a)—C(O)—or —C(O)—NR^(4a)— moiety, where R^(4a) is selected from H, —OH, and—C₁₋₄alkyl; R⁵ is selected from —C₀₋₃alkylene-SR^(5a),—C₀₋₃alkylene-C(O)NR^(5b)R^(5c), —C₀₋₃alkylene-NR^(5b)—C(O)R^(5d),—NH—C₀₋₁alkylene-P(O)(OR^(5e))₂, —C₀₋₃alkylene-P(O)OR^(5e)R^(5f),—C₀₋₂alkylene-CHR^(5g)—COOH, —C₀₋₃alkylene-C(O)NR^(5h)—CHR^(5i)—COOH,and —C₀₋₃alkylene-S—SR^(5j); R^(5a) is H or —C(O)—R^(5aa); R^(5aa) is—C₁₋₆alkyl, —C₀₋₆alkylene-C₃₋₇cycloalkyl, —C₀₋₆alkylenearyl,—C₀₋₆alkyleneheteroaryl, —C₀₋₆alkylenemorpholine,—C₀₋₆alkylenepiperazine-CH₃, —CH[N(R^(5ab))₂]-aa where aa is an aminoacid side chain, -2-pyrrolidine, —C₀₋₆alkylene-OR^(5ab),—O—C₀₋₆alkylenearyl, —C₁₋₂alkylene-OC(O)—C₁₋₆alkyl,—C₁₋₂alkylene-OC(O)—C₀₋₆alkylenearyl, or—O—C₁₋₂alkylene-OC(O)O—C₁₋₆alkyl; R^(5ab) is H or —C₁₋₆alkyl; R^(5b) isH, —OH, —OC(O)R^(5ba), —CH₂COOH, —O-benzyl, -pyridyl, or—OC(S)NR^(5bb)R^(5bc); R^(5ba) is H, —C₁₋₆alkyl, aryl, —OCH₂-aryl,—CH₂O-aryl, or —NR^(5bb)R^(5bc); R^(5bb) and R^(5ba) are independentlyselected from H and —C₁₋₄alkyl; R^(5c) is H, —C₁₋₆alkyl, or—C(O)—R^(5ca); R^(5a) is H, —C₁₋₆alkyl, —C₃₋₇cycloalkyl, aryl, orheteroaryl; R^(5d) is H, —C₁₋₄alkyl, —C₀₋₃alkylenearyl,—NR^(5da)R^(5db), —CH₂SH, or —O—C₁₋₆alkyl; R^(5da) and R^(5db) areindependently selected from H and —C₁₋₄alkyl; R^(5e) is H, —C₁₋₆alkyl,—C₁₋₃alkylenearyl, —C₁₋₃alkyleneheteroaryl, —C₃₋₇cycloalkyl,—CH(CH₃)—O—C(O)R^(5ea),

R^(5ea) is —O—C₁₋₆alkyl, —O—C₃₋₇cycloalkyl, —NR^(5eb)R^(5ec), or—CH(NH₂)CH₂COOCH₃; R^(5eb) and R^(5ec) are independently selected fromH, —C₁₋₄alkyl, and —C₁₋₃alkylenearyl, or are taken together as—(CH₂)₃₋₆—; R^(5f) is H, —C₁₋₄alkyl, —C₀₋₃alkylenearyl,—C₁₋₃alkylene-NR^(5fa)R^(5fb), or—C₁₋₃alkylene(aryl)-C₀₋₃alkylene-NR^(5fa)R^(5fb); R^(5fa) and R^(5fb)are independently selected from H and —C₁₋₄alkyl; R^(5g) is H,—C₁₋₆alkyl, —C₁₋₃alkylenearyl, or —CH₂—O—(CH₂)₂—O—CH₃; R^(5h) is H or—C₁₋₄alkyl; R^(5i) is H, —C₁₋₄alkyl, or —C₀₋₃alkylenearyl; and R^(5j) is—C₁₋₆alkyl, aryl, or —CH₂CH(NH₂)COOH; R⁶ is selected from —C₁₋₆alkyl,—CH₂—O—(CH₂)₂—O—CH₃, —C₁₋₆alkylene-O—C₁₋₆alkyl, —C₀₋₃alkylenearyl,—C₀₋₃alkyleneheteroaryl, and —C₀₋₃alkylene-C₃₋₇cycloalkyl; and R⁷ is Hor is taken together with R⁶ to form —C₃₋₈cycloalkyl; wherein: each—CH₂— group in —(CH₂)_(r)— is optionally substituted with 1 or 2substituents independently selected from —C₁₋₄alkyl and fluoro; eachring in Ar and each aryl and heteroaryl in R¹⁻³ and R⁵⁻⁶ is optionallysubstituted with 1 to 3 substituents independently selected from —OH,—C₁₋₆alkyl, —C₂₋₄alkenyl, —C₂₋₄alkynyl, —CN, halo, —O—C₁₋₆ alkyl, —S—C₁₋₆ alkyl, —S(O)—C₁₋₆ alkyl, —S(O)₂—C₁₋₄ alkyl, -phenyl, —NO₂, —NH₂,—NH—C₁₋₆alkyl and —N(C₁₋₆alkyl)₂, wherein each alkyl, alkenyl andalkynyl is optionally substituted with 1 to 5 fluoro atoms; each carbonatom in X is optionally substituted with one or more R^(4b) groups andone —CH₂— moiety in X may be replaced with a group selected from—C₄₋₈cycloalkylene-, —CR^(4d)═CH—, and —CH═CR^(4d)—; wherein R^(4b) isselected from —C₀₋₅alkylene-COOR^(4c), —C₁₋₆alkyl, —C₀₋₁alkylene-CONH₂,—C₁₋₂alkylene-OH, —C₀₋₃alkylene-C₃₋₇ cycloalkyl, 1H-indol-3-yl, benzyl,and hydroxybenzyl, where R^(4c) is H or —C₁₋₄alkyl; and R^(4d) isselected from —CH₂-2-thiophene and phenyl; each alkyl and each aryl inR¹⁻³, R^(4a-4d), and R⁵⁻⁶ is optionally substituted with 1 to 7 fluoroatoms; and pharmaceutically acceptable salts thereof.
 2. The compound ofclaim 1, wherein r is
 1. 3. The compound of claim 1, wherein Ar isselected from:


4. The compound of claim 1, wherein R¹ is selected from —COOH,—NHSO₂R^(1b), —SO₂NHR^(1d), —SO₂OH, —C(O)NH—SO₂R^(1c), —P(O)(OH)₂, —CN,—O—CH(R^(1e))—COOH, tetrazol-5-yl,


5. The compound of claim 4, wherein R¹ is selected from —COOH,—SO₂NHR^(1d), and tetrazol-5-yl.
 6. The compound of claim 1, wherein R¹is —COOR^(1a), where R^(1a) is selected from —C₁₋₆alkyl,—C₁₋₃alkylenearyl, —C₁₋₃alkyleneheteroaryl, —C₃₋₇cyclo alkyl,—CH(C₁₋₄alkyl)OC(O)R^(1aa), —C₀₋₆alkylenemorpholine,

7-10. (canceled)
 11. The compound of claim 1, wherein R² is selectedfrom H, halo, —C₁₋₆alkyl, —C₃₋₆cycloalkyl, and —C₀₋₅alkylene-OR^(2b).12. The compound of claim 1, wherein R³ is selected from —C₁₋₁₀alkyl and—C₀₋₅alkylene-O—C₀₋₅alkylene-R^(3b), where R^(3b) is —C₁₋₆alkyl.
 13. Thecompound of claim 12, wherein R³ is selected from —C₂₋₅alkyl and—O—C₁₋₅alkyl.
 14. The compound of claim 1, wherein X is —C₁₋₁₁alkylene-,1 to 4-CH₂-moieties in the alkylene are replaced with a —NR^(4a)—C(O)—or —C(O)—NR^(4a)— moiety, and R^(4a) is selected from H and —OH.
 15. Thecompound of claim 14 wherein X is selected from: —C(O)NH—; —CH₂—NHC(O)—;—C(O)NH—CH₂—; —C(O)NH—NHC(O)—; —CH═C(—CH₂-2-thiophene)-C(O)NH—;—(CH₂)₂—NHC(O)—; —C(O)NH—CH₂—CH(COOH)—CH₂—;—C(O)NH—CH(benzyl)-CH₂—NHC(O)—; —C(O)NH—CH(benzyl)-CH₂—C(O)NH—;—CH₂—NHC(O)—CH₂—NHC(O)—; —CH₂—NHC(O)-cyclohexylene-NHC(O)—;—CH₂—N(OH)C(O)-cyclohexylene-NHC(O)—; —CH₂—NHC(O)—CH₂—CH(COOH)—NHC(O)—;—CH₂—NHC(O)—(CH₂)₂—NHC(O)—; —C(O)NH—(CH₂)₂—C(O)N(OH)—CH₂—;—C(O)NH—(CH₂)₂—CH(COOH)—NHC(O)—; —C(O)NH—(CH₂)₄—NHC(O)—;—CH₂—NHC(O)—(CH₂)₂—CH(COOH)—NHC(O)—; —C(O)NH—(CH₂)₃—CH(COOH)—NHC(O)—;—C(O)NH—(CH₂)₂—NHC(O)—CH₂—NHC(O)—;—C(O)NH—(CH₂)₂—NHC(O)-cyclohexylene-NHC(O)—; —CH₂—NHC(O)—(CH₂)₄—NHC(O)—;—C(O)NH—(CH₂)₄—CH(COOH)—NHC(O)—;—CH₂—NHC(O)—(CH₂)₂—NHC(O)-cyclohexylene-NHC(O)—;—CH₂—C(O)NH—(CH₂)₂—NHC(O)-cyclohexylene-NHC(O)—;—C(O)NH—(CH₂)₄—NHC(O)—CH₂—NHC(O)—;—C(O)NH—(CH₂)₄—NHC(O)-cyclohexylene-NHC(O)—; —CH₂—NHC(O)—(CH₂)₆—NHC(O)—;—CH₂—NHC(O)—(CH₂)₄—NHC(O)-cyclohexylene-NHC(O)—;—C(O)NH—(CH₂)₆—NHC(O)-cyclohexylene-NHC(O)—; and—CH₂—NHC(O)—(CH₂)₆—NHC(O)-cyclohexylene-NHC(O)—.
 16. The compound ofclaim 15, wherein X is selected from —C(O)NH— and —CH₂—NHC(O)—.
 17. Thecompound of claim 1, wherein R⁵ is selected from —C₀₋₃alkylene-SR^(5a),—C₀₋₃alkylene-C(O)NR^(5b)R^(5c), —C₀₋₃alkylene-NR^(5b)—C(O)R^(5d),—NH—C₀₋₁alkylene-P(O)(OR^(5e))₂, —C₀₋₃alkylene-P(O)OR^(5e)R^(5f),—C₀₋₂alkylene-CHR^(5g)—COOH, and—C₀₋₃alkylene-C(O)NR^(5h)—CHR^(5i)—COOH; R^(5a) is H, R^(5b) is —OH,R^(5a) is H, R^(5d) is H, R^(5e) is H.
 18. The compound of claim 1,wherein R⁵ is selected from —C₀₋₃alkylene-SR^(5a),—C₀₋₃alkylene-C(O)NR^(5b)R^(5c), —C₀₋₃alkylene-NR^(5b)—C(O)R^(5d),—NH—C₀₋₁alkylene-P(O)(OR^(5e))₂, —C₀₋₃alkylene-P(O)OR^(5e)R^(5f), and—C₀₋₃alkylene-S—SR^(5j); where R^(5a) is —C(O)—R^(5aa); R^(5b) is H,—OC(O)R^(5ba), —CH₂COOH, —O-benzyl, -pyridyl, or —OC(S)NR^(5bb)R^(5bc);R^(5e) is —C₁₋₆alkyl, —C₁₋₃alkylenearyl, —C₁₋₃alkyleneheteroaryl,—C₃₋₇cycloalkyl, —CH(CH₃)—O—C(O)R^(5ea),


19. The compound of claim 17, wherein R¹ is selected from —COOH,—NHSO₂R^(1b), —SO₂NHR^(1d), —SO₂OH, —C(O)NH—SO₂R^(1c), —P(O)(OH)₂, —CN,—O—CH(R^(1e))—COOH, tetrazol-5-yl,


20. The compound of claim 18, wherein R¹ is —COOR^(1a), where R^(1a) is—C₁₋₆alkyl, —C₁₋₃alkylenearyl, —C₁₋₃alkyleneheteroaryl, —C₃₋₇cycloalkyl, —CH(C₁₋₄alkyl)OC(O)R^(1aa), —C₀₋₆alkylenemorpholine,


21. The compound of claim 17, wherein R¹ is —COOR^(1a), and R^(1a) is—C₁₋₆alkyl, —C₁₋₃alkylenearyl, —C₁₋₃alkyleneheteroaryl, —C₃₋₇cycloalkyl, —CH(C₁₋₄alkyl)OC(O)R^(1aa), —C₀₋₆alkylenemorpholine,


22. The compound of claim 18, wherein R¹ is selected from —COOH,—NHSO₂R^(1b), —SO₂NHR^(1d), —SO₂OH, —C(O)NH—SO₂R^(1c), —P(O)(OH)₂, —CN,—O—CH(R^(1e))—COOH, tetrazol-5-yl,


23. The compound of claim 1, wherein R⁶ is selected from —C₁₋₆alkyl,—C₀₋₃alkylenearyl, —C₀₋₃alkyleneheteroaryl, and—C₀₋₃alkylene-C₃₋₇cycloalkyl.
 24. The compound of claim 1, wherein R⁷ isH or is taken together with R⁶ to form cyclopentyl. 25.-26. (canceled)27. The compound of claim 1, having formula IVa:


28. The compound of claim 27, wherein Ar is:

R¹ is —COOR^(1a), where R^(1a) is H or —C₁₋₆alkyl; R² is H; R³ is—C₁₋₁₀alkyl; X is —CH₂—NHC(O)—; R⁵ is selected from—C₀₋₃alkylene-SR^(5a) and —C₀₋₃alkylene-C(O)N(OH)H; R^(5a) is H or—C(O)C₁₋₆alkyl; R⁶ is selected from —C₁₋₆alkyl and —C₀₋₃alkylenearyl;and R⁷ is H. 29-30. (canceled)
 31. A pharmaceutical compositioncomprising the compound of claim 1 and a pharmaceutically acceptablecarrier.
 32. The pharmaceutical composition of claim 31 furthercomprising a second therapeutic agent selected from the group consistingof diuretics, β₁ adrenergic receptor blockers, calcium channel blockers,angiotensin-converting enzyme inhibitors, AT₁ receptor antagonists,neprilysin inhibitors, non-steroidal anti-inflammatory agents,prostaglandins, anti-lipid agents, anti-diabetic agents, anti-thromboticagents, renin inhibitors, endothelin receptor antagonists, endothelinconverting enzyme inhibitors, aldosterone antagonists,angiotensin-converting enzyme/neprilysin inhibitors, vasopressinreceptor antagonists, and combinations thereof. 33-43. (canceled)